Compounds useful as inhibitors of ATR kinase

ABSTRACT

The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. 
     The compounds of this invention have formula I: 
                         
or a pharmaceutically acceptable salt, wherein the variables are as devined herein.
 
     Moreover, The compounds of this invention have formula I-A: 
                         
or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. application Ser.No. 14/098,606, filed on Dec. 6, 2013, issued as U.S. Pat. No.9,340,546, which claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 61/734,726, filed Dec. 7, 2012; U.S.Provisional Application No. 61/787,568, filed Mar. 15, 2013; and U.S.Provisional Application No. 61/868,132, filed Aug. 21, 2013, the entirecontents of each of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

ATR (“ATM and Rad3 related”) kinase is a protein kinase involved incellular responses to certain forms of DNA damage (e.g., double strandbreaks and replication stress). ATR kinase acts with ATM (“ataxiatelangiectasia mutated”) kinase and many other proteins to regulate acell's response to double strand DNA breaks and replication stress,commonly referred to as the DNA Damage Response (“DDR”). The DDRstimulates DNA repair, promotes survival and stalls cell cycleprogression by activating cell cycle checkpoints, which provide time forrepair. Without the DDR, cells are much more sensitive to DNA damage andreadily die from DNA lesions induced by endogenous cellular processessuch as DNA replication or exogenous DNA damaging agents commonly usedin cancer therapy.

Healthy cells can rely on a host of different proteins for DNA repairincluding the DDR kinases ATR and ATM. In some cases these proteins cancompensate for one another by activating functionally redundant DNArepair processes. On the contrary, many cancer cells harbour defects insome of their DNA repair processes, such as ATM signaling, and thereforedisplay a greater reliance on their remaining intact DNA repair proteinswhich include ATR.

In addition, many cancer cells express activated oncogenes or lack keytumour suppressors, and this can make these cancer cells prone todysregulated phases of DNA replication which in turn cause DNA damage.ATR has been implicated as a critical component of the DDR in responseto disrupted DNA replication. As a result, these cancer cells are moredependent on ATR activity for survival than healthy cells. Accordingly,ATR inhibitors may be useful for cancer treatment, either used alone orin combination with DNA damaging agents, because they shut down a DNArepair mechanism that is more important for cellular survival in manycancer cells than in healthy normal cells.

In fact, disruption of ATR function (e.g. by gene deletion) has beenshown to promote cancer cell death both in the absence and presence ofDNA damaging agents. This suggests that ATR inhibitors may be effectiveboth as single agents and as potent sensitizers to radiotherapy orgenotoxic chemotherapy.

ATR peptide can be expressed and isolated using a variety of methodsknown in the literature (see e.g., Ünsal-Kaçmaz et al, PNAS 99: 10,pp6673-6678, May 14, 2002; see also Kumagai et al. Cell 124, pp943-955,Mar. 10, 2006; Unsal-Kacmaz et al. Molecular and Cellular Biology,February 2004, p 1292-1300; and Hall-Jackson et al. Oncogene 1999, 18,6707-6713).

For all of these reasons, there is a need for the development of potentand selective ATR inhibitors for the treatment of cancer, either assingle agents or as combination therapies with radiotherapy or genotoxicchemotherapy.

SUMMARY OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ATRprotein kinase. The invention also relates to pharmaceuticallyacceptable compositions comprising the compounds of this invention;methods of treating of various diseases, disorders, and conditions usingthe compounds of this invention; processes for preparing the compoundsof this invention; intermediates for the preparation of the compounds ofthis invention; and methods of using the compounds in in vitroapplications, such as the study of kinases in biological andpathological phenomena; the study of intracellular signal transductionpathways mediated by such kinases; and the comparative evaluation of newkinase inhibitors.

The compounds of the invention are very potent ATR inhibitors. Thesecompounds also show surprising synergy with other cancer agents, such ascisplatin and gemcitabine, in combination therapies.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from —C(J¹)₂CN, halo, -(L)_(k)-W, or M;-   R⁹ is independently selected from H, —C(J¹)₂CN, halo, -(L)_(k)-W, or    M;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form a 3-4 membered optionally substituted carbocyclic    ring;-   k is 0 or 1;-   M and L are a C₁₋₈aliphatic wherein up to three methylene units are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—, each M    and L¹ is optionally substituted with 0-3 occurrences of J^(LM);-   J^(LM) is independently selected from halo, —CN, or a C₁₋₄aliphatic    chain wherein up to two methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—;-   W is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring having 0-3    heteroatoms selected from oxygen, nitrogen or sulfur; or a 7-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen,    or sulfur; wherein W is optionally substituted with 0-5 occurrences    of J^(W);-   J^(W) is independently selected from —CN, halo, —CF₃; a    C₁₋₄aliphatic wherein up to two methylene units are optionally    replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—; or a 3-6 membered    non-aromatic ring having 0-2 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   two occurrences of J^(W) on the same atom, together with atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; or-   two occurrences of J^(W), together with W, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   R² is independently selected from H; halo; —CN; NH₂; a C₁₋₂alkyl    optionally substituted with 0-3 occurrences of fluoro; or a    C₁₋₃aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n);-   R³ is independently selected from H; halo; C₁₋₄alkyl optionally    substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl; 3-4    membered heterocyclyl; —CN; or a C₁₋₃aliphatic chain wherein up to    two methylene units of the aliphatic chain are optionally replaced    with —O—, —NR—, —C(O)—, or —S(O)_(n);-   R⁴ is independently selected from Q¹ or a C₁₋₁₀aliphatic chain    wherein up to four methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—; each R⁴    is optionally substituted with 0-5 occurrences of J^(Q); or-   R³ and R⁴, taken together with the atoms to which they are bound,    form a 5-6 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen or sulfur; the ring    formed by R³ and R⁴ is optionally substituted with 0-3 occurrences    of J^(Z);-   Q¹ is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring, the 3-7 membered    ring having 0-3 heteroatoms selected from oxygen, nitrogen or    sulfur; or an 7-12 membered fully saturated, partially unsaturated,    or aromatic bicyclic ring having 0-5 heteroatoms selected from    oxygen, nitrogen, or sulfur;-   J^(z) is independently selected from C₁₋₆aliphatic, ═O, halo, or →O;-   J^(Q) is independently selected from —CN; halo; ═O; Q²; or a    C₁₋₈aliphatic chain wherein up to three methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; each occurrence of J^(Q) is optionally substituted by    0-3 occurrences of J^(R); or-   two occurrences of J^(Q) on the same atom, taken together with the    atom to which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the    ring formed by two occurrences of J^(Q) is optionally substituted    with 0-3 occurrences of J^(X); or-   two occurrences of J^(Q), together with Q¹, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   Q² is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring having 0-3    heteroatoms selected from oxygen, nitrogen, or sulfur; or an 7-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(R) is independently selected from —CN; halo; ═O; →O; Q³; or a    C₁₋₆aliphatic chain wherein up to three methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; each J^(R) is optionally substituted with 0-3    occurrences of J^(T); or-   two occurrences of J^(R) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   wherein the ring formed by two occurrences of J^(R) is optionally    substituted with 0-3 occurrences of J^(X); or-   two occurrences of J^(R), together with Q², form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   Q³ is a 3-7 membered fully saturated, partially unsaturated, or    aromatic monocyclic ring having 0-3 heteroatoms selected from    oxygen, nitrogen, or sulfur; or an 7-12 membered fully saturated,    partially unsaturated, or aromatic bicyclic ring having 0-5    heteroatoms selected from oxygen, nitrogen, or sulfur;-   J^(X) is independently selected from —CN; ═O; halo; or a    C₁₋₄aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—;-   J^(T) is independently selected from halo, —CN; →O; ═O; —OH; a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; each    occurrence of J^(T) is optionally substituted with 0-3 occurrences    of J^(M); or-   two occurrences of J^(T) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; or-   two occurrences of J^(T), together with Q³, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   J^(M) is independently selected from halo or C₁₋₆aliphatic;-   n is 0, 1 or 2; and-   R is independently selected from H or C₁₋₄aliphatic.

In another embodiment, the present invention is a compound of formula I,wherein R⁹ is H.

In one or more aspects, the present invention is a compound of formulaI, wherein R⁹ is M. In another aspect, the present invention is acompound of formula I, wherein M is a C₁₋₈aliphatic wherein up to threemethylene units are optionally replaced with —O— or —NR—. In someaspects, the present invention is a compound of formula I, wherein M isC₁₋₄alkyl, —(C₁₋₄alkyl)O(C₁₋₃aliphatic), —(C₁₋₃alkyl)OH,—O(C₁₋₄alkyl)N(C₁₋₂alkyl)₂, —NH(C₁₋₄alkyl), or—(C₁₋₄alkyl)NH(C₁₋₄alkyl). In yet another aspect, the present inventionis a compound of formula I, wherein M is C₁₋₄alkyl.

In one or more embodiments, the present invention is a compound offormula I, wherein J^(LM) is halo.

In some embodiments, the present invention is a compound of formula I,wherein R⁹ is -(L)_(k)-W.

In another example, the present invention is a compound of formula I,wherein k is 1. In other examples, the present invention is a compoundof formula I, wherein k is 0.

In one or more aspects, the present invention is a compound of formulaI, wherein L is a C₁₋₈aliphatic wherein up to three methylene units areoptionally replaced with —O— or —NR—. In other aspects of the invention,the present invention is a compound of formula I, wherein L is —O—,—O(C1-4aliphatic)-, or —NR(C₁₋₃alkyl)-.

In one or more embodiments, the present invention is a compound offormula I, wherein W is a 3-7 membered fully saturated, partiallyunsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selectedfrom oxygen, nitrogen or sulfur. In some embodiments, the presentinvention is a compound of formula I, wherein W is a 3-7 memberedheterocyclyl. In another embodiment, the present invention is a compoundof formula I, wherein W is independently selected from pyrrolidinyl,piperidinyl, piperazinyl, oxetanyl, or azetidinyl.

In other embodiments, the present invention is a compound of formula I,wherein W is a 7-12 membered fully saturated, partially unsaturated, oraromatic bicyclic ring having 0-5 heteroatoms selected from oxygen,nitrogen, or sulfur. In yet another embodiment, the present invention isa compound of formula I, wherein W is octahydropyrrolo[1,2-a]pyrazine.

In some aspects, the present invention is a compound of formula I,wherein J^(W) is selected form C₁₋₃alkyl or CF₃. In other aspects, thepresent invention is a compound of formula I, wherein two occurrences ofJ^(W) on the same atom, together with atom to which they are joined,form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen,nitrogen, or sulfur. In yet another aspect, the present invention is acompound of formula I, wherein the ring formed by the two occurrences ofJ^(W) on the same atom is oxetanyl.

Another aspect of the invention provides a compound of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from fluoro, chloro, or —C(J¹)₂CN;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form a 3-4 membered optionally substituted carbocyclic    ring;-   R² is independently selected from H; halo; —CN; NH₂; a C₁₋₂alkyl    optionally substituted with 0-3 occurrences of fluoro; or a    C₁₋₃aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n);-   R³ is independently selected from H; halo; C₁₋₄alkyl optionally    substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl; —CN; or a    C₁₋₃aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n);-   R⁴ is independently selected from Q¹ or a C₁₋₁₀aliphatic chain    wherein up to four methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—; each R⁴    is optionally substituted with 0-5 occurrences of J^(Q); or-   R³ and R⁴, taken together with the atoms to which they are bound,    form a 5-6 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen or sulfur; the ring    formed by R³ and R⁴ is optionally substituted with 0-3 occurrences    of J^(Z);-   Q¹ is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring, the 3-7 membered    ring having 0-3 heteroatoms selected from oxygen, nitrogen or    sulfur; or an 7-12 membered fully saturated, partially unsaturated,    or aromatic bicyclic ring having 0-5 heteroatoms selected from    oxygen, nitrogen, or sulfur;-   J^(z) is independently selected from C₁₋₆aliphatic, ═O, halo, or →O;-   J^(Q) is independently selected from —CN; halo; ═O; Q²; or a    C₁₋₈aliphatic chain wherein up to three methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; each occurrence of J^(Q) is optionally substituted by    0-3 occurrences of J^(R); or-   two occurrences of J^(Q) on the same atom, taken together with the    atom to which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the    ring formed by two occurrences of J^(Q) is optionally substituted    with 0-3 occurrences of J^(X); or-   two occurrences of J^(Q), together with Q¹, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   Q² is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring having 0-3    heteroatoms selected from oxygen, nitrogen, or sulfur; or an 7-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(R) is independently selected from —CN; halo; ═O; →O; Q³; or a    C₁₋₆aliphatic chain wherein up to three methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; each J^(R) is optionally substituted with 0-3    occurrences of J^(T); or-   two occurrences of J^(R) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the    ring formed by two occurrences of J^(R) is optionally substituted    with 0-3 occurrences of J^(X); or-   two occurrences of J^(R), together with Q², form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   Q³ is a 3-7 membered fully saturated, partially unsaturated, or    aromatic monocyclic ring having 0-3 heteroatoms selected from    oxygen, nitrogen, or sulfur; or an 7-12 membered fully saturated,    partially unsaturated, or aromatic bicyclic ring having 0-5    heteroatoms selected from oxygen, nitrogen, or sulfur;-   J^(X) is independently selected from —CN; ═O; halo; or a    C₁₋₄aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—;-   J^(T) is independently selected from halo, —CN; →O; ═O; —OH; a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; each    occurrence of J^(T) is optionally substituted with 0-3 occurrences    of J^(M); or-   two occurrences of J^(T) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; or-   two occurrences of J^(T), together with Q³, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   J^(M) is independently selected from halo or C₁₋₆aliphatic;-   n is 0, 1 or 2; and-   R is independently selected from H or C₁₋₄aliphatic.

Another aspect of the invention provides a compound of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from fluoro, chloro, or —C(J¹)₂CN;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form a 3-4 membered optionally substituted carbocyclic    ring;-   R² is independently selected from H; halo; —CN; NH₂; a C₁₋₂alkyl    optionally substituted with 0-3 occurrences of fluoro; or a    C₁₋₃aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—;-   R³ is independently selected from H; halo; C₁₋₄alkyl optionally    substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl; —CN; or a    C₁₋₃aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n);-   R⁴ is independently selected from Q¹ or a C₁₋₁₀aliphatic chain    wherein up to four methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—; each R⁴    is optionally substituted with 0-5 occurrences of J^(Q); or-   R³ and R⁴, taken together with the atoms to which they are bound,    form a 5-6 membered non-aromatic ring having 0-2 heteroatoms    selected from oxygen, nitrogen or sulfur; the ring formed by R³ and    R⁴ is optionally substituted with 0-3 occurrences of J^(Z);-   Q¹ is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring, the 3-7 membered    ring having 0-3 heteroatoms selected from oxygen, nitrogen or    sulfur; or an 7-12 membered fully saturated, partially unsaturated,    or aromatic bicyclic ring having 0-5 heteroatoms selected from    oxygen, nitrogen, or sulfur;-   J^(z) is independently selected from C₁₋₆aliphatic, ═O, halo, or →O;-   J^(Q) is independently selected from —CN; halo; ═O; Q²; or a    C₁₋₈aliphatic chain wherein up to three methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; each occurrence of J^(Q) is optionally substituted by    0-3 occurrences of J^(R); or-   two occurrences of J^(Q) on the same atom, taken together with the    atom to which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the    ring formed by two occurrences of J^(Q) is optionally substituted    with 0-3 occurrences of J^(X); or-   two occurrences of J^(Q), together with Q¹, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   Q² is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring having 0-3    heteroatoms selected from oxygen, nitrogen, or sulfur; or an 7-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(R) is independently selected from —CN; halo; ═O; →O; Q³; or a    C₁₋₆aliphatic chain wherein up to three methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n)—; each J^(R) is optionally substituted with 0-3    occurrences of J^(T); or-   two occurrences of J^(R) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   wherein the ring formed by two occurrences of J^(R) is optionally    substituted with 0-3 occurrences of J^(X); or-   two occurrences of J^(R), together with Q², form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   Q³ is a 3-7 membered fully saturated, partially unsaturated, or    aromatic monocyclic ring having 0-3 heteroatoms selected from    oxygen, nitrogen, or sulfur; or an 7-12 membered fully saturated,    partially unsaturated, or aromatic bicyclic ring having 0-5    heteroatoms selected from oxygen, nitrogen, or sulfur;-   J^(X) is independently selected from —CN; halo; or a C₁₋₄aliphatic    chain wherein up to two methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—;-   J^(T) is independently selected from —CN; ═O; —OH; a C₁₋₆aliphatic    chain wherein up to two methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n)—; or a 3-6    membered non-aromatic ring having 0-2 heteroatoms selected from    oxygen, nitrogen, or sulfur; each occurrence of J^(T) is optionally    substituted with 0-3 occurrences of J^(M); or-   two occurrences of J^(T) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; or-   two occurrences of J^(T), together with Q³, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   J^(M) is independently selected from halo or C₁₋₆aliphatic;-   n is 0, 1 or 2; and-   R is independently selected from H or C₁₋₄aliphatic.

Another aspect of the invention provides a compound of formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from fluoro, chloro, or —C(J¹)₂CN;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form an optionally substituted 3-4 membered    carbocyclic ring;-   R² is independently selected from H; chloro; NH₂; or a C₁₋₂alkyl    optionally substituted with fluoro;-   R³ is independently selected from H; chloro; fluoro; C₁₋₄alkyl    optionally substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl;    or —CN;-   R⁴ is independently selected from Q¹ or a C₁₋₁₀aliphatic chain    wherein up to three methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, or —S—; each R⁴ is optionally    substituted with 0-5 occurrences of J^(Q); or-   R³ and R⁴, taken together with the atoms to which they are bound,    form a 5-6 membered non-aromatic ring having 0-2 heteroatoms    selected from oxygen, nitrogen or sulfur; the ring formed by R³ and    R⁴ is optionally substituted with 0-3 occurrences of J^(Z);-   Q¹ is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring having 0-3    heteroatoms selected from oxygen, nitrogen or sulfur; or an 7-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring; having 0-5 heteroatoms selected from oxygen,    nitrogen, or sulfur;-   J^(z) is independently selected from C₁₋₆aliphatic, ═O, halo, or →O;-   J^(Q) is independently selected from halo; ═O; Q²; or a    C₁₋₈aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—,    or —S(O)_(n)—; each occurrence of J^(Q) is optionally substituted by    0-3 occurrences of J^(R); or-   two occurrences of J^(Q) on the same atom, taken together with the    atom to which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the    ring formed by two occurrences of J^(Q) is optionally substituted    with 0-3 occurrences of J^(X); or-   two occurrences of J^(Q), together with Q¹, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   Q² is independently selected from a 3-7 membered fully saturated,    partially unsaturated, or aromatic monocyclic ring having 0-3    heteroatoms selected from oxygen, nitrogen, or sulfur; or an 8-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(R) is independently selected from halo; ═O; →O; a 3-7 membered    fully saturated, partially unsaturated, or aromatic monocyclic ring    having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or    a C₁₋₄aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—,    or —S(O)_(n)—; each J^(R) is optionally substituted with 0-3    occurrences of J^(T); or-   two occurrences of J^(R) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the    ring formed by two occurrences of J^(R) is optionally substituted    with 0-3 occurrences of J^(X); or-   two occurrences of J^(R), together with Q², form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   J^(X) is independently selected from halo or a C₁₋₄aliphatic chain    wherein up to two methylene units of the aliphatic chain are    optionally replaced with —O—, —NR—, —S—, —C(O)—, or —S(O)_(n)—; or-   J^(T) is independently selected from a C₁₋₆aliphatic or a 3-6    membered non-aromatic ring having 0-2 heteroatoms selected from    oxygen, nitrogen, or sulfur; each occurrence of J^(T) is optionally    substituted with 0-3 occurrences of J^(M);-   J^(M) is independently selected from halo or C₁₋₆aliphatic;-   n is 1 or 2; and-   R is independently selected from H or C₁₋₄aliphatic.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein R¹ is fluoro. In anotherembodiment, the present invention is a compound represented bystructural formula I or I-A, wherein R¹ is —CH₂CN. In another embodimentR¹ is —CH(C₁₋₂alkyl)CN. In another embodiment, the present invention isa compound represented by structural formula I or I-A, wherein R¹ isC(CH₃)₂CN. In yet another embodiment, the present invention is acompound represented by structural formula I or I-A, wherein R¹ ischloro.

In one example, the present invention is a compound represented bystructural formula I or I-A, wherein R² is independently selected from—CF₃, —NH(C₁₋₂alkyl), chloro, or H. In another example, the presentinvention is a compound represented by structural formula I or I-A,wherein R² is H. In other examples, the present invention is a compoundrepresented by structural formula I or I-A, wherein R² is -chloro.

In yet another embodiment, the present invention is a compoundrepresented by structural formula I or I-A, wherein R³ is independentlyselected from H, chloro, fluoro, CHF₂, —CN, cyclopropyl, or C₁₋₄alkyl.In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein R³ is independently selected fromH, chloro, or fluoro. In another embodiment, the present invention is acompound represented by structural formula I or I-A, wherein R³ is H. Inanother embodiment, the present invention is a compound represented bystructural formula I or I-A, wherein R³ is —O(C₁₋₂alkyl). In otherembodiments, the present invention is a compound represented bystructural formula I or I-A, wherein R³ is chloro. In yet anotherembodiment, the present invention is a compound represented bystructural formula I or I-A, wherein R³ is fluoro.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein R⁴ is independently selected from:

—O—;

or —CH₂—R⁷, wherein:

-   —O— is substituted with one J^(Q);-   Ring A is independently selected from a 3-7 membered fully    saturated, partially unsaturated, or aromatic monocyclic ring having    1-3 heteroatoms selected from oxygen, nitrogen or sulfur; or an 7-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring having 1-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   Ring B is independently selected from a 3-7 membered fully    saturated, partially unsaturated, or aromatic monocyclic ring having    0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or an 7-12    membered fully saturated, partially unsaturated, or aromatic    bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   R⁶ is H;-   R⁷ is independently selected from H or a C₁₋₈aliphatic chain wherein    up to three methylene units of the aliphatic chain are optionally    replaced with —O—, —NR—, —S—, —C(O)—, or —S(O)_(n)—; and-   p is 0 or 1.

In one example, the present invention is a compound represented bystructural formula I or I-A, wherein R⁴ is —O—. In some examples, thepresent invention is a compound represented by structural formula I orI-A, wherein when R⁴ is —O—, J^(Q) is independently selected from—(C₁₋₄alkyl), —(C₁₋₄alkyl)N(C₁₋₄alkyl)₂,—(C₁₋₃alkyl)O(C₁₋₂alkyl)N(C₁₋₃alkyl)₂, (C₁₋₄alkyl)OH, —(C₁₋₄alkyl)NH₂,or —(C₁₋₄alkyl)O(C₁₋₄alkyl).

In another example, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, J^(Q) is Q². In yetanother example, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is a 3-7membered fully saturated, partially unsaturated, or aromatic monocyclicring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen.

In other embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is independentlyselected from a 5-6 membered aryl, a 5-6 membered heteroaryl, a 4-6membered cycloaliphatic, or a 4-7 membered heterocyclyl. In yet anotherembodiment, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is a 4-7membered heterocyclyl. In yet another embodiment, the present inventionis a compound represented by structural formula I or I-A, wherein whenR⁴ is —O—, Q² is independently selected from pyrrolidinyl, piperidinyl,azepanyl, pyrazolidinyl, isoxazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,1,3-oxazinanyl, 1,3-thiazinanyl, dihydropyridinyl, dihydroimidazolyl,1,3-tetrahydropyrimidinyl, dihydropyrimidinyl, 1,4-diazepanyl,1,4-oxazepanyl, 1,4-thiazepanyl, tetrahydrothiopyranyl,tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, and oxetanyl. In someembodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is independentlyselected from tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl,piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, or azetidinyl. Inother embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is piperidinyl.

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is —O—, Q² is a 5-6membered heteroaryl. In some embodiments, the present invention is acompound represented by structural formula I or I-A, wherein when R⁴ is—O—, Q² is independently selected from imidazolyl, pyrrolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyrazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl.In yet another embodiment, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is —O—, Q²is pyridinyl.

In another example, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is a 4-6membered cycloaliphatic. In yet another example, the present inventionis a compound represented by structural formula I or I-A, wherein whenR⁴ is —O—, Q² is independently selected from cyclobutyl or cyclohexyl.In other examples, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is phenyl.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is an 8-12membered fully saturated, partially unsaturated, or aromatic bicyclicring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur.In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q² is a 7-12membered fully saturated, partially unsaturated, or aromatic bicyclicring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur.In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is —O—, Q² is6,7-dihydro-5H-pyrrolo[1,2-a]imidazole.

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is —O—, J^(R) is aC₁₋₆aliphatic chain wherein up to two methylene units of the aliphaticchain are optionally replaced with —O—, —NR—, —S—, —C(O)—, or—S(O)_(n)—. In other embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is —O—,J^(R) is independently selected from C₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —C(O)OH,—C(O)O(C₁₋₄alkyl), —C(O)N(C₁₋₄alkyl)₂, —(C₁₋₄alkyl)O(C₁₋₄alkyl), or—C(O)—. In still other embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is —O—,J^(R) is C₁₋₄alkyl.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, J^(R) is a 3-6membered fully saturated, partially unsaturated, or aromatic monocyclicring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen.In yet another embodiment, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is —O—,J^(R) is a 3-6 membered heterocyclyl having 1-3 heteroatoms selectedfrom oxygen, nitrogen, or sulfur. In another embodiment, the presentinvention is a compound represented by structural formula I or I-A,wherein when R⁴ is —O—, J^(R) is independently independently selectedfrom oxetanyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl,morpholinyl. In other embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is —O—,J^(R) is oxetanyl. In still other embodiments, the present invention isa compound represented by structural formula I or I-A, wherein when R⁴is —O—, J^(R) is cyclopropyl.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, J^(R) is Q³. Inanother embodiment, the present invention is a compound represented bystructural formula I or I-A, wherein Q³ is a 3-6 membered fullysaturated, partially unsaturated, or aromatic monocyclic ring having 0-3heteroatoms selected from oxygen, sulfur, or nitrogen. In yet anotherembodiment, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q³ is a 3-6membered heterocyclyl having 1-3 heteroatoms selected from oxygen,nitrogen, or sulfur. In another embodiment, the present invention is acompound represented by structural formula I or I-A, wherein when R⁴ is—O—, Q³ is independently independently selected from oxetanyl,piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl. Inother embodiments, when R⁴ is —O—, Q³ is oxetanyl. In still otherembodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, Q³ is cyclopropyl.

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is —O—, J^(R) is ═O orhalo.

In other embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, two occurrences ofJ^(R) on the same atom, taken together with the atom to which they arejoined, form a 3-6 membered non-aromatic ring having 0-2 heteroatomsselected from oxygen, nitrogen, or sulfur. In yet another embodiment,the present invention is a compound represented by structural formula Ior I-A, wherein when R⁴ is —O—, the ring formed by the two occurrencesof J^(R) on the same atom, taken together with the atom to which theyare joined, is selected from oxetanyl, cyclobutyl, or azetidinyl.

In other examples, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is —O—, J^(T) is a 4-6membered heterocyclyl ring having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur. In some examples, the present invention is acompound represented by structural formula I or I-A, wherein when R⁴ is—O—, J^(T) is piperazinyl.

In another example, the compounds of formula I and I-A of this inventionare represented in Table 1. It will be appreciated by those skilled inthe art that the compounds of the present invention may be representedin varying tautomeric forms.

TABLE 1

I-O-1

I-O-2

I-O-3

I-O-4

I-O-5

I-O-6

I-O-7

I-O-8

I-O-9

I-O-10

I-O-11

I-O-12

I-O-13

I-O-14

I-O-15

I-O-16

I-O-17

I-O-18

I-O-19

I-O-20

I-O-21

I-O-22

I-O-23

I-O-24

I-O-25

I-O-26

I-O-27

I-O-28

I-O-29

I-O-30

I-O-31

I-O-32

I-O-33

I-O-34

I-O-35

I-O-36

I-O-37

I-O-38

I-O-39

I-O-40

I-O-41

I-O-42

I-O-43

I-O-44

I-O-45

I-O-46

I-O-47

I-O-48

I-O-49

I-O-50

I-O-51

I-O-52

I-O-53

I-O-54

I-O-55

I-O-56

I-O-57

I-O-58

I-O-59

I-O-60

I-O-61

I-O-62

I-O-63

I-O-64

I-O-65

I-O-66

I-O-67

I-O-68

I-O-69

I-O-70

I-O-71

I-O-72

I-O-73

I-O-74

I-O-75

I-O-76

I-O-77

I-O-78

I-O-79

I-O-80

I-O-81

I-O-82

I-O-83

I-O-84

I-O-85

I-O-86

I-O-87

I-O-88

I-O-89

I-O-90

I-O-91

I-O-92

In another example, the present invention is a compound represented bystructural formula I or I-A, wherein R⁴ is Ring A, which is representedby the structure:

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein Ring A is a is a 3-7 membered fullysaturated, partially unsaturated, or aromatic monocyclic ring having 1-3heteroatoms selected from oxygen, nitrogen or sulfur. In otherembodiments, the present invention is a compound represented bystructural formula I or I-A, wherein Ring A is a 4-6 memberedheterocyclyl. In other embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein Ring A is a 3-7membered heterocyclyl. In still other embodiments, the present inventionis a compound represented by structural formula I or I-A, wherein Ring Ais independently selected from pyrrolidinyl, piperidinyl, azepanyl,pyrazolidinyl, isoxazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,1,3-oxazinanyl, 1,3-thiazinanyl, dihydropyridinyl, dihydroimidazolyl,1,3-tetrahydropyrimidinyl, dihydropyrimidinyl, 1,4-diazepanyl,1,4-oxazepanyl, 1,4-thiazepanyl, and azetidinyl. In yet anotherembodiment, the present invention is a compound represented bystructural formula I or I-A, wherein Ring A is independently selectedfrom piperidinyl, piperazinyl, 1,4-diazepanyl, thiomorpholinyl,pyrrolidinyl, azepanyl, and morpholinyl. In some embodiments, thepresent invention is a compound represented by structural formula I orI-A, wherein Ring A is independently selected from piperazinyl orpiperidinyl.

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein Ring A is a 5 memberedheteroaryl. In other embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein Ring A isindependently selected from pyrrolyl, imidazolyl, pyrazolyl,1,2,3-triazolyl, or 1,2,4-triazolyl. In still other embodiments, thepresent invention is a compound represented by structural formula I orI-A, wherein Ring A is independently selected from pyrazolyl orimidazolyl.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein Ring A is a 7-12 membered fullysaturated, partially unsaturated, or aromatic bicyclic ring having 1-5heteroatoms selected from oxygen, nitrogen, or sulfur. In anotherexample, the present invention is a compound represented by structuralformula I or I-A, wherein Ring A is independently selected fromoctahydropyrrolo[1,2-a]pyrazinyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl,octahydro-1H-pyrazino[1,2-a]pyrazinyl,5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl, 2,5-diazabicyclo[4.1.0], oroctahydropyrazino[2,1-c][1,4]oxazinyl.

In yet another embodiment, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is Ring A,J^(Q) is C₁₋₈aliphatic chain wherein up to two methylene units of thealiphatic chain are optionally replaced with —O—, —NR—, or —C(O)—. Inyet another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is Ring A, J^(Q) is aC₁₋₆aliphatic chain wherein up to two methylene units of the aliphaticchain are optionally replaced with —O—, —NR—, or —C(O)—. In someembodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, J^(Q) isindependently selected from —O—, —C(O)—, —S(O)₂—, C₁₋₄alkyl,—(C₀₋₄alkyl)NH₂, —(C₀₋₄alkyl)NH(C₁₋₄alkyl), —(C₀₋₄alkyl)N(C₁₋₄alkyl)₂,—(C₀₋₄alkyl)OH, —(C₀₋₄alkyl)O(C₁₋₄alkyl), —C(O)OH, —S(O)₂N(C₁₋₃alkyl)-,—C(O)(C₁₋₄alkyl)-, —(O)C(C₁₋₄alkyl)N(C₁₋₂alkyl)₂ or —C(O)O(C₁₋₄alkyl).In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, J^(Q) isindependently selected from —C(O)—, C₁₋₄alkyl, —(C₀₋₄alkyl)NH₂,—(C₀₋₄alkyl)NH(C₁₋₄alkyl), —(C₀₋₄alkyl)N(C₁₋₄alkyl)₂, —(C₀₋₄alkyl)OH,—(C₀₋₄alkyl)O(C₁₋₄alkyl), —C(O)OH, —C(O)O(C₁₋₄alkyl). In still otherembodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, J^(Q) isC₁₋₄alkyl. In still other embodiments, the present invention is acompound represented by structural formula I or I-A, wherein when R⁴ isRing A, J^(Q) is C₁ alkyl, —O—, or —C(O)—.

In one or more examples, when R⁴ is Ring A, J^(Q) is Q².

In another example, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, Q² is a 3-7membered heterocyclyl or carbocyclyl; the heterocyclyl having 1-3heteroatoms selected from oxygen, nitrogen, or sulfur. In otherexamples, the present invention is a compound represented by structuralformula I or I-A, wherein when R⁴ is Ring A, Q² is independentlyselected from selected from oxetanyl, tetrahydropyranyl,tetrahydrofuranyl, cyclopropyl, azetidinyl, pyrrolidinyl, piperazinyl,cyclobutyl, thiomorpholinyl, or morpholinyl. In yet other examples, thepresent invention is a compound represented by structural formula I orI-A, wherein when R⁴ is Ring A, Q² is independently selected fromoxetanyl, tetrahydropyranyl, or tetrahydrofuranyl. In some examples, thepresent invention is a compound represented by structural formula I orI-A, wherein when R⁴ is Ring A, Q² is oxetanyl.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, Q² is a 7-12membered fully saturated, partially unsaturated, or aromatic bicyclicring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur.In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, Q² is an 8-12membered fully saturated, partially unsaturated, or aromatic bicyclicring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur.In another example, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, Q² isindependently selected from 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl or5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl.

In yet another embodiment, the present invention is a compoundrepresented by structural formula I or I-A, wherein two occurrences ofJ^(Q), together with Ring A, form a bridged ring system.

In other embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, J^(Q) is ═O.

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is Ring A, J^(R) is a3-6 membered heterocyclyl having 1-3 heteroatoms selected from oxygen,nitrogen, or sulfur. In still other embodiments, the present inventionis a compound represented by structural formula I or I-A, wherein whenR⁴ is Ring A, J^(R) is independently selected from oxetanyl,piperadinyl, azetidinyl, piperazinyl, pyrrolidinyl, or morpholinyl. Inyet another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is Ring A, J^(R) is apiperazinyl.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, J^(R) isindependently selected from halo, ═O, —OH, C₁₋₄alkyl,—(C₀₋₄alkyl)N(C₁₋₄alkyl)₂, or —(C₀₋₄alkyl)O(C₁₋₄alkyl).

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when R⁴ is Ring A, twooccurrences of J^(R) on the same atom, together with the atom to whichthey are joined, form a 3-6 membered aromatic or non-aromatic ringhaving 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur. Inother embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring A, J^(R) isindependently selected from oxetanyl or azetidinyl.

In yet another embodiment, the present invention is a compoundrepresented by structural formula I or I-A, wherein two occurrences ofJ^(R), together with Ring A, form a bridged ring system.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein J^(T) is a 3-6 memberednon-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen,or sulfur. In other embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein J^(T) is oxytanyl.In another embodiment, J^(T) is a C₁₋₆aliphatic. In another embodiment,J^(T) is methyl.

Another aspect of the present invention provides a compound of formulaI-A-1:

wherein:

-   R⁵ is selected from C₁₋₄aliphatic, a 3-6 membered cycloalkyl, or a    3-6 membered heterocyclyl having 1-2 heteroatoms selected from    oxygen or sulfur;-   R⁸ is selected from H or C₁₋₃ alkyl; or-   R⁵ and R⁸, taken together with the atoms to which they are bound,    form a 5-6 membered non-aromatic ring having 1-2 heteroatoms    selected from oxygen, nitrogen or sulfur.

In another embodiment, the present invention is a compound representedby structural formula I-A-1, wherein R¹ in formula I-A-1 is fluoro.

In another example, the present invention is a compound represented bystructural formula I-A-1, wherein R⁵ is C₁ aliphatic. In yet otherembodiments, the present invention is a compound represented bystructural formula I-A-1, wherein R⁵ is independently selected frommethyl or ethyl.

In some embodiments, the present invention is a compound represented bystructural formula I-A-1, wherein R⁵ is a 3-6 membered cycloalkyl. Inother embodiments, the present invention is a compound represented bystructural formula I-A-1, wherein R⁵ is cyclopropyl.

In yet another embodiment, the present invention is a compoundrepresented by structural formula I-A-1, wherein R⁵ is a 3-6 memberedheterocyclyl having 1-2 heteroatoms selected from oxygen or sulfur. Insome embodiments, the present invention is a compound represented bystructural formula I-A-1, wherein R⁵ is tetrahydrofuranyl or oxetanyl.

In other embodiments, the present invention is a compound represented bystructural formula I-A-1, wherein R⁵ and R⁸, taken together with theatoms to which they are bound, form a 5-6 membered non-aromatic ringhaving 1-2 heteroatoms selected form oxygen, nitrogen or sulfur. Inanother embodiment, the present invention is a compound represented bystructural formula I-A-1, wherein the ring formed by R⁵ and R⁸ is afive-membered ring. In yet another embodiment, the present invention isa compound represented by structural formula I-A-1, wherein the ringformed by R⁵ and R⁸ is a six-membered ring.

In another example, the compounds of formula I, I-A, and I-A-1 of thisinvention are represented in Table 2.

TABLE 2

I-N-1

I-N-2

I-N-3

I-N-4

I-N-5

I-N-6

I-N-7

I-N-8

I-N-9

I-N-10

I-N-11

I-N-12

I-N-13

I-N-14

I-N-15

I-N-16

I-N-17

I-N-18

I-N-19

I-N-20

I-N-21

I-N-22

I-N-23

I-N-24

I-N-25

I-N-26

I-N-27

I-N-28

I-N-29

I-N-30

I-N-31

I-N-32

I-N-33

I-N-34

I-N-35

I-N-36

I-N-37

I-N-38

I-N-39

I-N-40

I-N-41

I-N-42

I-N-43

I-N-44

I-N-45

I-N-46

I-N-47

I-N-48

I-N-49

I-N-50

I-N-51

I-N-52

I-N-53

I-N-54

I-N-55

I-N-56

I-N-57

I-N-58

I-N-59

I-N-60

I-N-61

I-N-62

I-N-63

I-N-64

I-N-65

I-N-66

I-N-67

I-N-68

I-N-69

I-N-70

I-N-71

I-N-72

I-N-73

I-N-74

I-N-75

I-N-76

I-N-77

I-N-78

I-N-79

I-N-80

I-N-81

I-N-82

I-N-83

I-N-84

I-N-85

I-N-86

I-N-87

I-N-88

I-N-89

I-N-90

I-N-91

I-N-92

I-N-93

I-N-94

I-N-95

I-N-96

I-N-97

I-N-98

I-N-99

I-N-100

I-N-101

I-N-102

I-N-103

I-N-104

I-N-105

I-N-106

I-N-107

I-N-108

I-N-109

I-N-110

I-N-111

I-N-112

I-N-113

I-N-114

I-N-115

I-N-116

I-N-117

I-N-118

I-N-119

I-N-120

I-N-121

I-N-122

I-N-123

I-N-124

I-N-125

I-N-126

I-N-127

I-N-128

I-N-129

I-N-130

I-N-131

I-N-132

I-N-133

I-N-134

I-N-135

I-N-136

I-N-137

I-N-138

I-N-139

I-N-140

I-N-141

I-N-142

I-N-143

I-N-144

I-N-145

I-N-146

I-N-147

I-N-148

I-N-149

I-N-150

I-N-151

I-N-152

I-N-153

I-N-154

I-N-155

I-N-156

I-N-157

I-N-158

I-N-159

I-N-160

I-N-161

I-N-162

I-N-163

I-N-164

I-N-165

I-N-166

I-N-167

I-N-168

I-N-169

I-N-170

I-N-171

I-N-172

I-N-173

I-N-174

I-N-175

I-N-176

I-N-177

I-N-178

I-N-179

I-N-180

I-N-181

I-N-182

I-N-183

I-N-184

I-N-185

I-N-186

I-N-187

I-N-188

I-N-189

I-N-190

I-N-191

I-N-192

I-N-193

I-N-194

I-N-195

I-N-196

I-N-197

I-N-198

I-N-199

I-N-200

I-N-201

I-N-202

I-N-203

I-N-204

I-N-205

I-N-206

I-N-207

I-N-208

I-N-209

I-N-210

I-N-211

I-N-212

I-N-213

I-N-214

I-N-215

I-N-216

I-N-217

I-N-218

I-N-219

I-N-220

I-N-221

I-N-222

I-N-223

I-N-224

I-N-225

I-N-226

I-N-227

I-N-228

I-N-229

I-N-230

I-N-231

I-N-232

I-N-233

I-N-234

I-N-235

I-N-236

I-N-237

I-N-238

I-N-239

I-N-240

I-N-241

I-N-242

I-N-243

I-N-244

I-N-245

I-N-246

I-N-247

I-N-248

I-N-249

I-N-250

I-N-251

I-N-252

I-N-253

I-N-254

I-N-255

I-N-256

I-N-257

I-N-258

I-N-259

I-N-260

I-N-261

I-N-262

I-N-263

I-N-264

I-N-265

I-N-266

I-N-267

I-N-268

I-N-269

I-N-270

I-N-271

I-N-272

I-N-273

I-N-274

I-N-275

I-N-276

I-N-277

I-N-278

I-N-279

I-N-280

I-N-281

I-N-282

I-N-283

I-N-284

I-N-285

I-N-286

I-N-287

I-N-288

I-N-289

I-N-290

In other embodiments, the compounds of the present invention areselected from one of the following:

In another example, the present invention is a compound represented bystructural formula I or I-A, wherein R⁴ is Ring B, which is representedby the structure:

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein p is 1.

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein when p is 1, Ring B is a 3-7membered cycloaliphatic or heterocyclyl ring having 1-2 heteroatomsselected from oxygen, nitrogen or sulfur. In other embodiments, thepresent invention is a compound represented by structural formula I orI-A, wherein when p is 1, Ring B is independently selected from selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,pyrrolidinyl, piperidinyl, azepanyl, pyrazolidinyl, isoxazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, dihydropyridinyl,dihydroimidazolyl, 1,3-tetrahydropyrimidinyl, dihydropyrimidinyl,1,4-diazepanyl, 1,4-oxazepanyl, 1,4-thiazepanyl,1,2,3,6-tetrahydropyridine, and azetidinyl. In still other embodiments,the present invention is a compound represented by structural formula Ior I-A, wherein Ring B is piperidinyl.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when R⁴ is Ring B, J^(Q) is —C(O)—or C₁₋₄alkyl. In some embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is Ring B,J^(Q) is C₁₋₄alkyl.

In yet another embodiment, the present invention is a compoundrepresented by structural formula I or I-A, wherein when R⁴ is Ring B,J^(Q) is Q². In some embodiments, when R⁴ is Ring B, the presentinvention is a compound represented by structural formula I or I-A,wherein Q² is independently selected from Q² is independently selectedfrom oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, cyclopropyl,azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, cyclobutyl,thiomorpholinyl, or morpholinyl. In other embodiments, the presentinvention is a compound represented by structural formula I or I-A,wherein when R⁴ is Ring B, Q² is oxetanyl.

In one embodiment, the present invention is a compound represented bystructural formula I or I-A, wherein p is 0.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when p is 0, Ring B isindependently selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl,tetrahydropyridinyl, pyridizinyl, or pyrazolyl. In yet anotherembodiment, the present invention is a compound represented bystructural formula I or I-A, wherein when p is 0, Ring B is imidazolyl.In other embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein when p is 0, Ring B isindependently selected from phenyl or pyridinyl.

In another embodiment, the present invention is a compound representedby structural formula I or I-A, wherein R⁴ is —CH₂—(R⁷). In yet anotherembodiment, the present invention is a compound represented bystructural formula I or I-A, wherein R⁷ is H.

In still other embodiments, the present invention is a compoundrepresented by structural formula I or I-A, wherein R³ and R⁴, takentogether with the atoms to which they are bound, form a 5-6 memberednon-aromatic ring having 0-2 heteroatoms selected from oxygen.

In some embodiments, the present invention is a compound represented bystructural formula I or I-A, wherein J^(Z) is independently selectedfrom →O or C₁₋₄alkyl.

In another example, the present invention is a compound represented bystructural formula I or I-A, wherein the compounds of this invention arerepresented in Table 3.

TABLE 3

I-C-1

I-C-2

I-C-3

I-C-4

I-C-5

I-C-6

I-C-7

I-C-8

I-C-9

I-C-10

I-C-11

I-C-12

I-C-13

I-C-14

I-C-15

I-C-16

I-C-17

I-C-18

I-C-19

I-C-20

I-C-21

I-C-22

I-C-23

I-C-24

I-C-25

I-C-26

I-C-27

I-C-28

I-C-29

I-C-30

I-C-31

I-C-32

I-C-33

I-C-34

I-C-35

I-C-36

I-C-37

I-C-38

I-C-39

I-C-40

I-C-41

I-C-42

I-C-43

I-C-44

I-C-45

I-C-46

I-C-47

I-C-48

I-C-49

I-C-50

I-C-51

I-C-52

I-C-53

I-C-54

I-C-55

I-C-56

I-C-57

I-C-58

I-C-59

I-C-60

I-C-61

I-C-62

I-C-63

I-C-64

I-C-65

I-C-66

I-C-67

I-C-68

I-C-69

I-C-70

I-C-71

I-C-72

I-C-73

I-C-74

I-C-75

I-C-76

I-C-77

I-C-78

I-C-79

I-C-80

I-C-81

I-C-82

I-C-83

I-C-84

In another embodiment, the compounds of the present invention areselected from one of the following:

A compound having the formula I-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from fluoro, chloro, or —C(J¹)₂CN;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form an optionally substituted 3-4 membered    carbocyclic ring;-   R³ is independently selected from H; chloro; fluoro; C₁₋₄alkyl    optionally substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl;    —CN; or a C₁₋₃aliphatic chain wherein up to two methylene units of    the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—,    or —S(O)_(n);-   L¹ is H; a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen nitrogen or sulfur; or a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n); each L¹ is optionally substituted with C₁₋₄aliphatic;    —CN; halo; —OH; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L² is H; a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen nitrogen or sulfur; or a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n); each L² is optionally substituted with C₁₋₄aliphatic;    —CN; halo; —OH; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; or-   L¹ and L², together with the nitrogen to which they are attached,    form a Ring D; Ring D is optionally substituted with 0-5 occurrences    of J^(G);-   Ring D is independently selected from a 3-7 membered heterocyclyl    ring having 1-2 heteroatoms selected from oxygen, nitrogen or    sulfur; or an 7-12 membered fully saturated or partially unsaturated    bicyclic ring having 1-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(G) is independently selected from halo; —N(R^(o))₂; a 3-6    membered carbocycyl; a 3-6 membered heterocyclyl having 1-2    heteroatoms selected from oxygen nitrogen, or sulfur; or a C₁₋₄alkyl    chain wherein up to two methylene units of the alkyl chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n); each J^(G)    is optionally substituted with 0-2 occurrences of J^(K).-   two occurrences of J^(G) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   two occurrences of J^(G), together with Ring D, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   J^(K) is a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L³ is independently selected from H; chloro; fluoro; C₁₋₄alkyl    optionally substituted with 1-3 occurrences of halo; —CN; or a    C₁₋₃aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n);-   n is 0, 1, or 2; and-   R and R^(o) are H or C₁₋₄alkyl.

Another aspect of the present invention provides a compound of FormulaI-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from fluoro, chloro, or —C(J¹)₂CN;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form an optionally substituted 3-4 membered    carbocyclic ring;-   R³ is independently selected from H; chloro; fluoro; C₁ alkyl    optionally substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl;    —CN; or a C₁₋₃aliphatic chain wherein up to two methylene units of    the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—,    or —S(O)_(n);-   L¹ is H; a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen nitrogen or sulfur; or a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n); each L¹ is optionally substituted with C₁₋₄aliphatic;    —CN; halo; —OH; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L² is H; a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen nitrogen or sulfur; or a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n); each L² is optionally substituted with C₁₋₄aliphatic;    —CN; halo; —OH; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; or-   L¹ and L², together with the nitrogen to which they are attached,    form a Ring D; Ring D is optionally substituted with 0-5 occurrences    of J^(G);-   Ring D is independently selected from a 3-7 membered heterocyclyl    ring having 1-2 heteroatoms selected from oxygen, nitrogen or    sulfur; or an 7-12 membered fully saturated or partially unsaturated    bicyclic ring having 1-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(G) is independently selected from halo; —CN; —N(R^(o))₂; a 3-6    membered carbocycyl; a 3-6 membered heterocyclyl having 1-2    heteroatoms selected from oxygen nitrogen, or sulfur; or a C₁₋₄alkyl    chain wherein up to two methylene units of the alkyl chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n); each J^(G)    is optionally substituted with 0-2 occurrences of J^(K).-   two occurrences of J^(G) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   two occurrences of J^(G), together with Ring D, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   J^(K) is a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   n is 0, 1, or 2; and-   R and R^(o) are H or C₁₋₄alkyl.

Another aspect of the present invention provides a compound of FormulaI-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from fluoro, chloro, or —C(J¹)₂CN;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form an optionally substituted 3-4 membered    carbocyclic ring;-   R³ is independently selected from H; chloro; fluoro; C₁₋₄alkyl    optionally substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl;    —CN; or a C₁₋₃aliphatic chain wherein up to two methylene units of    the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—,    or —S(O)_(n);-   L¹ is H; a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen nitrogen or sulfur; or a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n); each L¹ is optionally substituted with C₁₋₄aliphatic;    —CN; halo; —OH; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   L² is H; a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen nitrogen or sulfur; or a    C₁₋₆aliphatic chain wherein up to two methylene units of the    aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or    —S(O)_(n); each L² is optionally substituted with C₁₋₄aliphatic;    —CN; halo; —OH; or a 3-6 membered non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur; or-   L¹ and L², together with the nitrogen to which they are attached,    form a Ring D; Ring D is optionally substituted with 0-5 occurrences    of J^(G);-   Ring D is independently selected from a 3-7 membered heterocyclyl    ring having 1-2 heteroatoms selected from oxygen, nitrogen or    sulfur; or an 7-12 membered fully saturated or partially unsaturated    bicyclic ring having 1-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(G) is independently selected from halo; →O; —CN; —N(R^(o))₂; a    3-6 membered carbocycyl; a 3-6 membered heterocyclyl having 1-2    heteroatoms selected from oxygen nitrogen, or sulfur; or a C₁₋₄alkyl    chain wherein up to two methylene units of the alkyl chain are    optionally replaced with —O—, —NR—, —C(O)—, or —S(O)_(n); each J^(G)    is optionally substituted with 0-2 occurrences of J^(K).-   two occurrences of J^(G) on the same atom, together with the atom to    which they are joined, form a 3-6 membered ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   two occurrences of J^(G), together with Ring D, form a 6-10 membered    saturated or partially unsaturated bridged ring system;-   J^(K) is a 3-7 membered aromatic or non-aromatic ring having 0-2    heteroatoms selected from oxygen, nitrogen, or sulfur;-   n is 0, 1, or 2; and-   R and R^(o) are H or C₁₋₄alkyl.

Another aspect of the present invention provides a compound of FormulaI-B:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

-   R¹ is independently selected from fluoro, chloro, or —C(J¹)₂CN;-   J¹ is independently selected from H or C₁₋₂alkyl; or-   two occurrences of J¹, together with the carbon atom to which they    are attached, form an optionally substituted 3-4 membered    carbocyclic ring;-   R³ is independently selected from H; chloro; fluoro; C₁₋₄ alkyl    optionally substituted with 1-3 occurrences of halo; C₃₋₄cycloalkyl;    or —CN;-   L¹ is an optionally substituted C₁₋₆aliphatic;-   L² is an optionally substituted C₁₋₆aliphatic; or-   L¹ and L², together with the nitrogen to which they are attached,    form a Ring D; Ring D is optionally substituted with 0-5 occurrences    of J^(G);-   Ring D is independently selected from a 3-7 membered heterocyclyl    ring having 1-2 heteroatoms selected from oxygen, nitrogen or    sulfur; or an 8-12 membered fully saturated or partially unsaturated    bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen,    or sulfur;-   J^(G) is independently selected from C₁₋₄alkyl, —N(R^(o))₂, or a 3-5    membered carbocycyl; or-   two occurrences of J^(G), together with Ring D, form a 6-10 membered    saturated or partially unsaturated bridged ring system; and-   R^(o) is H or C₁₋₄alkyl.

In another example, R¹ of formula I-B is fluoro. In yet another example,R¹ of formula I-B is —CH₂CN. In still other examples, R¹ of formula I-Bis chloro.

In some embodiments, R³ of formula I-B is independently selected from H,chloro, fluoro, cyclopropyl, or C₁₋₄alkyl. In one or more embodiments,R³ of formula I-B is independently selected from H, chloro, or fluoro.In yet another embodiment, R³ of formula I-B is H. In other embodiments,R³ of formula I-B is chloro. In still other embodiments, R³ of formulaI-B is fluoro.

In another embodiment, the present invention is a compound representedby structural formula I-B, wherein L¹ and L² are independently selectedfrom H; —(C₁₋₃alkyl)O(C₁₋₂alkyl); —(C₁₋₃alkyl)N(C₁₋₂alkyl)₂; C₁₋₄alkyl;azetidinyl; piperidinyl; oxytanyl; or pyrrolidinyl. In anotherembodiment, the present invention is a compound represented bystructural formula I-B, wherein L¹ and L² are C₁₋₃alkyl.

In other embodiments, the present invention is a compound represented bystructural formula I-B, wherein L¹ and L², together with the nitrogen towhich they are attached, form Ring D. In yet another embodiment, thepresent invention is a compound represented by structural formula I-B,wherein Ring D is a 3-7 membered heterocyclyl ring having 1-2heteroatoms selected from oxygen, nitrogen, or sulfur. In someembodiments, the present invention is a compound represented bystructural formula I-B, wherein Ring D is independently selected frompiperazinyl, piperidinyl, morpholinyl, tetrahydopyranyl, azetidinyl,pyrrolidinyl, or 1,4-diazepanyl. In another embodiment, the presentinvention is a compound represented by structural formula I-B, whereinRing D is piperazinyl, piperidinyl, 1,4-diazepanyl, pyrrolidinyl orazetidinyl. In still other embodiments, the present invention is acompound represented by structural formula I-B, wherein Ring D ispiperidinyl or piperazinyl. In still other embodiments, Ring D ispiperazinyl.

In one or more aspects, the present invention is a compound representedby structural formula I-B, wherein Ring D is an 8-12 membered fullysaturated or partially unsaturated bicyclic ring having 0-5 heteroatomsselected from oxygen, nitrogen, or sulfur. In other examples, thepresent invention is a compound represented by structural formula I-B,wherein Ring D is octahydropyrrolo[1,2-a]pyrazine oroctahydropyrrolo[3,4-c]pyrrole. In another example, Ring D isoctahydropyrrolo[1,2-a]pyrazine.

In yet another example, the present invention is a compound representedby structural formula I-B, wherein J^(G) is halo, C₁₋₄alkyl,—O(C₁₋₃alkyl), C₃₋₆cycloalkyl, a 3-6 membered heterocyclyl,—NH(C₁₋₃alkyl), —OH, or —N(C₁₋₄alkyl)₂. In other embodiments, thepresent invention is a compound represented by structural formula I-B,wherein J^(G) is methyl, —N(C₁₋₄alkyl)₂, ethyl, —O(C₁₋₃alkyl),cyclopropyl, oxetanyl, cyclobutyl, pyrrolidinyl, piperidinyl, orazetidinyl. In still other embodiments, the present invention is acompound represented by structural formula I-B, wherein J^(G) is methyl,—O(C₁₋₃alkyl), oxetanyl, pyrrolidinyl, piperidinyl, or azetidinyl. Inyet another example, the present invention is a compound represented bystructural formula I-B, wherein J^(G) is C₁₋₄alkyl, C₃₋₅cycloalkyl, or—N(C₁₋₄alkyl)₂. In other embodiments, the present invention is acompound represented by structural formula I-B, wherein J^(G) is methyl,ethyl, or cyclopropyl. In some embodiments, the present invention is acompound represented by structural formula I-B, wherein J^(G) is methyl.In still other embodiments, the present invention is a compoundrepresented by structural formula I-B, wherein J^(G) is oxetanyl.

In another example, the present invention is a compound represented bystructural formula I-B, wherein two occurrences of J^(G), together withRing D, form a 6-10 membered saturated or partially unsaturated bridgedring system. In some examples, the present invention is a compoundrepresented by structural formula I-B, wherein the bridged ring systemis 1,4-diazabicyclo[3.2.2]nonane, 1,4-diazabicyclo[3.2.1]octane, or2,5-diazabicyclo[2.2.1]heptane. In some examples, the present inventionis a compound represented by structural formula I-B, wherein the bridgedring system is 1,4-diazabicyclo[3.2.2]nonane.

In some embodiments, the present invention is a compound represented bystructural formula I-B, wherein two occurrences of J^(G) on the sameatom, together with the atom to which they are joined, form a 3-6membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, orsulfur. the present invention is a compound represented by structuralformula I-B, wherein In other embodiments, the ring formed by the twooccurrences of J^(G) on the same atom is selected from oxetanyl orcyclopropyl

In another example, the present invention is a compound represented bystructural formula I, I-A, and I-B, wherein the compounds of thisinvention are represented in Table 4.

TABLE 4

I-G-1

I-G-2

I-G-3

I-G-4

I-G-5

I-G-6

I-G-7

I-G-8

I-G-9

I-G-10

I-G-11

I-G-12

I-G-13

I-G-14

I-G-15

I-G-16

I-G-18

I-G-19

I-G-20

I-G-21

I-G-22

I-G-23

I-G-24

I-G-25

I-G-26

I-G-27

I-G-28

I-G-29

I-G-30

I-G-31

I-G-32

I-G-33

I-G-34

I-G-35

I-G-36

I-G-37

I-G-38

I-G-40

I-G-41

I-G-42

I-G-43

I-G-44

I-G-45

I-G-46

I-G-47

I-G-48

I-G-49

I-G-50

I-G-51

I-G-52

I-G-53

I-G-54

I-G-55

I-G-56

I-G-57

I-G-58

I-G-59

I-G-60

I-G-61

I-G-62

I-G-63

I-G-64

I-G-65

I-G-66

I-G-67

I-G-68

I-G-69

I-G-70

I-G-71

I-G-72

I-G-73

I-G-74

I-G-75

I-G-76

I-G-77

I-G-78

I-G-79

I-G-80

I-G-81

I-G-82

I-G-83

I-G-84

I-G-85

I-G-86

I-G-87

I-G-88

I-G-89

I-G-90

I-G-91

I-G-92

I-G-93

I-G-94

I-G-95

I-G-96

I-G-98

I-G-99

In another embodiment, the compound of the present invention is selectedfrom one of the following:

Preferably, the compound has the structure I-G-32:

or a pharmaceutically acceptable salt.

Another aspect of the present invention comprises a process forpreparing a compound of formula I-A:

-   -   comprising reacting a compound of formula 6:

-   -   under suitable conditions to form an amide bond, wherein J, R¹,        R², R³, and R⁴ are as defined herein.

In some examples, the suitable conditions for forming the amide bondcomprises reacting the compound of formula 6 with a substituted 3-aminopyridine in an aprotic solvent under heat. In other examples, theaprotic solvent is selected from NMP, optionally substituted pyridine,or DMF. In another embodiment, the aprotic solvent is optionallysubstituted pyridine. In still other embodiments, the reactiontemperature is at least 80° C. In another embodiment, the reactiontemperature is at least 100° C.

In another embodiment, the process, described above, further comprisespreparing a compound of formula 6:

-   -   by reacting a compound of formula 5:

-   -   under suitable conditions to form an activated ester, wherein J        and R¹ is as defined herein.

In some embodiments, suitable conditions for forming the activated estercomprises reacting the compound of formula 5 with an amide couplingagent in the presence of an organic base. In other embodiments, theorganic base is an aliphatic amine. In still other embodiments, theorganic base is independently selected from triethylamine or DIPEA. Inone or more embodiments, the amide coupling agent is independentlyselected from EDCI, TBTU, TCTU, HATU, T3P, or COMU. In yet anotherembodiment, the amide coupling agent is independently selected from TBTUor TCTU. In another embodiment, the amide coupling agent is TCTU.

Another aspect of the invention comprises a process for preparing acompound of formula I-A:

-   -   comprising reacting a compound of formula 5:

-   -   under suitable conditions to form an amide bond, wherein R¹, R²,        R³, and R⁴ are as defined herein.

Yet another aspect of the present invention comprises a process forpreparing a compound of formula 5:

-   -   by reacting a compound of formula 4:

-   -   under suitable hydrolytic conditions, wherein R¹ is as defined        herein.

In some embodiments, suitable hydrolytic conditions comprise reactingthe compound of formula 4 with a silane in the presence of a metalcatalyst. In other embodiments, the silane is a phenylsilane. In anotherembodiment, the metal catalyst is a palladium catalyst. In yet anotherembodiment, the palladium catalyst is Pd(PPh₃)₄. In another embodimentsuitable hydrolytic conditions comprise reacting the compound of formula4 with 4-methylbenzenesulfinate in the presence of a metal catalyst.

In still other embodiments, suitable hydrolytic conditions comprisereacting the compound of formula 4 with an aqueous alkali. In someembodiments, the aqueous alkali is selected from LiOH, NaOH or KOH.

Another aspect of the present invention comprises a process forpreparing a compound of formula 4:

-   -   by reacting a compound of formula 3:

-   -   under suitable condensation conditions to form a pyrimidine        ring.

In some embodiments, suitable condensation conditions to form apyrimidine ring comprise reacting the compound of formula 3 with a1,3-dielectrophilic species in the presence of a solvent. In anotherembodiment, the 1,3-dielectrophilic species is selected from1,3-dialdehyde or 3-(dialkylamino)-prop-2-enal. In still otherembodiments, the solvent is selected from DMF or DMSO in water. In otherembodiments, the 1,3-dielectrophilic species is generated in situ from aprotected 1,3-dielectrophilic species. In another embodiment the1,3-dielectrophilic species is generated from a ketal in the presence ofa sulfonic acid. In yet another embodiment, the sulfonic acid is PTSA.

Another aspect of the present invention comprises a process forpreparing the compound of formula 3:

-   -   by reacting a compound of formula 2:

-   -   under suitable condensation conditions to form a pyrazole ring.

In some embodiments, suitable condensation conditions to form a pyrazolering comprise reacting the compound of formula 2 with a hydrazine orhydrazine hydrate in the presence of an aprotic solvent under basicconditions. In another embodiment, the aprotic solvent is DMF. In yetanother embodiment, the basic conditions comprise reacting the compoundof formula 2 in the presence of potassium acetate or sodium acetate.

Yet another aspect of the present invention comprises a process forpreparing a compound of formula 2:

-   -   by reacting a compound of formula 1:

-   -   under suitable anion condensation conditions.

In some embodiments, suitable anion condensation conditions comprise 1)reacting the compound of formula 1 with a base, in the presence of asolvent, to generate the anion of the compound of formula 1; and 2)reacting the anion of the compound of formula 1 withtrichloroacetonitrile. In still other embodiments, the base is potassiumacetate. In yet another embodiment, the solvent is an alcohol. In otherembodiments, the solvent is isopropylalcohol.

One embodiment of the present invention comprises a process forpreparing a compound of formula I-A:

-   -   comprising reacting a compound of formula 9:

-   -   under suitable condensation conditions to form a pyrimidine        ring, wherein R¹, R², R³ and R⁴ are as defined herein.

In some embodiments, suitable condensation conditions to form apyrimidine ring comprise reacting the compound of formula 9 with a1,3-dielectrophilic species in the presence of a solvent. In anotherembodiment, the 1,3-dielectrophilic species is selected from1,3-dialdehyde or 3-(dialkylamino)-prop-2-enal. In still otherembodiments, the solvent is selected from DMF or DMSO in water. In otherembodiments, the 1,3-dielectrophilic species is generated in situ from aprotected 1,3-dielectrophlic species. In another embodiment the1,3-dielectrophilic species is generated from a ketal in the presence ofa sulfonic acid. In yet another embodiment, the sulfonic acid is PTSA.

Another embodiment of the present invention comprises a process forpreparing a compound of formula 9:

-   -   by reacting a compound of formula 8:

-   -   under suitable condensation conditions to form a pyrazole ring.

In some embodiments, suitable condensation conditions to form a pyrazolering comprise 1) reacting the compound of formula 8 with a base, in thepresence of a solvent, to generate the anion of the compound of formulaI; 2) reacting the anion with trichloroacetonitrile; and 3) reacting theproduct from 2) with a hydrazine or hydrazine hydrate in the presence ofan aprotic solvent. In another embodiment, the aprotic solvent is NMP orDMF. In some embodiments, the base is selected from sodium acetate orpotassium acetate.

Yet another embodiment comprises a process for preparing a compound offormula 8:

-   -   by reacting a compound of formula 7:

-   -   under suitable conditions to form an amide bond.

In some examples, the suitable conditions for forming the amide bondcomprises reacting the compound of formula 7 with a substituted 3-aminopyridine with an amide coupling agent in the presence of an aproticsolvent and an organic base. In other examples, the aprotic solvent isselected from NMP or DMF. In another embodiment, the organic base is analiphatic amine. In still other embodiments, the organic base isindependently selected from triethylamine or DIPEA. In yet anotherembodiment, the amide coupling agent is independently selected from TBTUor TCTU.

Another aspect of the present invention provides a process of preparinga compound of formula I-G-32:

-   -   comprising the step of reacting the compound of formula 29:

-   -   with a compound of formula 25:

-   -   under suitable conditions to form an amide bond.

Still other embodiments of the present invention comprise provides aprocess for preparing the compound of formula 29:

-   -   by reacting the compound of formula 28:

-   -   under suitable deprotection conditions to form the carboxylic        acid.

Another embodiment provides a process for preparing a compound offormula 28:

-   -   by reacting the compound of formula 6a*:

-   -   with a compound of formula 27:

-   -   under suitable conditions to form an amide bond.

In some embodiments, suitable conditions for forming the amide bondcomprise reacting the compound of formula 29 with the compound offormula 25 in the presence of an amide coupling partner, an aproticsolvent, and a base. In other embodiments, the aprotic solvent isindependently selected from NMP, DMF, or tetrahydrofuran. In still otherembodiments, the aprotic solvent is tetrahydrofuran. In anotherembodiment, the base is an aliphatic amine. In yet another embodiment,the base is DIPEA. In some embodiments, the amide coupling partner isindependently selected from TBTU or TCTU. In one or more embodiments,the amide coupling partner is TCTU.

In other embodiments, suitable deprotection conditions comprise reactingthe compound of formula 28 with an acid in the presence of a solvent. Insome embodiments, the acid is HCl. In another embodiment, the solvent is1,4-dioxane.

In yet another embodiment, suitable conditions for forming the amidebond comprise reacting the compound of formula 6a* with the compound offormula 27 in an aprotic solvent under heat. In still other embodiments,the aprotic solvent is independently selected from NMP, pyridine, orDMF. In another embodiment, the aprotic solvent is pyridine. In someembodiments, the reaction is carried out at a temperature of at least80° C.

Another aspect of the present invention provides a process of preparinga compound of formula 27:

-   -   comprising the step of reacting a compound of formula 26:

-   -   under suitable conditions to form an amine.

In some embodiments, suitable conditions to form an amine comprisereacting the compound of formula 27 under Buchwald-Hartwig aminationconditions, known to those skilled in the art.

Yet another embodiment provides a process for preparing a compound offormula 26:

-   -   by 1) reacting a compound of formula 18:

-   -   under suitable halogen exchange conditions to generate the        compound of formula 32

-   and

2) reacting the compound of formula 32:

-   -   with a compound of formula 22:

-   -   under suitable displacement conditions.

In some embodiments, suitable halogen exchange conditions comprisereacting the compound of formula 18 with potassium fluoride in thepresence of an aprotic solvent and a phase transfer catalyst. In otherembodiments, the aprotic solvent is independently selected from DMSO,DMF, or sulfolane. In still other embodiments, the phase transfercatalyst is Me₄NCl. In still other embodiments, suitable displacementconditions comprise reacting the compound of formula 32 with a compoundof formula 22 in the presence of a base. In another embodiment, the baseis an aliphatic amine. In some embodiments, the aliphatic amine isDIPEA.

Other embodiments of the present invention provides a process forpreparing a compound of formula 18:

-   -   by reacting the compound of formula 31:

-   -   under suitable halogenation conditions.

In some embodiments, suitable halogenation conditions comprise 1)reacting the compound of formula 31 with a base to generate an anion;and 2) reacting the anion with a chlorinating agent. In yet anotherembodiment, the base is LDA. In another embodiment, the chlorinatingagent is 1,1,1,2,2,2-hexachloroethane.

For purposes of this application, it will be understood that the termsembodiment, example, and aspect are used interchangeably.

For purposes of this application, it will be understood that when twooccurrences of J^(Q), together with Q¹, form a bridged ring system, thetwo occurrences of J^(Q) are attached to separate atoms of Q¹.Additionally, when two occurrences of J^(R), together with Q², form abridged ring system, the two occurrences of J^(R) are attached toseparate atoms of Q². Moreover, when two occurrences of J^(T), togetherwith Q³, form a bridged ring system, the two occurrence of J^(T) areattached to separate atoms of Q³. Further, when two occurrences ofJ^(W), together with W, form a bridged ring system, the two occurrencesof J^(W) are attached to separate atoms of W. Finally, when twooccurrences of J^(G), together with Ring D, form a bridged ring system,the two occurrences of J^(G) are attached to separate atoms of Ring D.

It will be understood by those skilled in the art that the arrow in →Orepresents a dative bond.

Compounds of this invention include those described generally herein,and are further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, a specified number range of atoms includes anyinteger therein. For example, a group having from 1-4 atoms could have1, 2, 3, or 4 atoms.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally herein, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

Unless otherwise indicated, a substituent connected by a bond drawn fromthe center of a ring means that the substituent can be bonded to anyposition in the ring. In example i below, for instance, J^(w) can bebonded to any position on the pyridyl ring. For bicyclic rings, a bonddrawn through both rings indicates that the substituent can be bondedfrom any position of the bicyclic ring. In example ii below, forinstance, J^(w) can be bonded to the 5-membered ring (on the nitrogenatom, for instance), and to the 6-membered ring.

The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, recovery, purification, and use for one or moreof the purposes disclosed herein. In some embodiments, a stable compoundor chemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or less, in the absence of moistureor other chemically reactive conditions, for at least a week.

The term “dative bond”, as used herein, is defined as the coordinationbond formed upon interaction between molecular species, one of whichserves as a donor and the other as an acceptor of the electron pair tobe shared in the complex formed.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched), branched, or cyclic, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation that has a single point ofattachment to the rest of the molecule.

Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groupsmay be linear or branched, substituted or unsubstituted alkyl, alkenyl,or alkynyl groups. Specific examples include, but are not limited to,methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl,ethynyl, and tert-butyl. Aliphatic groups may also be cyclic, or have acombination of linear or branched and cyclic groups. Examples of suchtypes of aliphatic groups include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, —CH₂-cyclopropyl,CH₂CH₂CH(CH₃)-cyclohexyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl”) refers to amonocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members. Examples of cycloaliphatic groups include, butare not limited to, cycloalkyl and cycloalkenyl groups. Specificexamples include, but are not limited to, cyclohexyl, cyclopropyl, andcyclobutyl.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic, or tricyclic ring systems inwhich one or more ring members are an independently selected heteroatom.In some embodiments, the “heterocycle”, “heterocyclyl”, or“heterocyclic” group has three to fourteen ring members in which one ormore ring members is a heteroatom independently selected from oxygen,sulfur, nitrogen, or phosphorus, and each ring in the system contains 3to 7 ring members.

Examples of heterocycles include, but are not limited to,3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl,2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl,4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g. cycloaliphatic and heterocycles), can be linearlyfused, bridged, or spirocyclic.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation. As would be known by one of skill in theart, unsaturated groups can be partially unsaturated or fullyunsaturated. Examples of partially unsaturated groups include, but arenot limited to, butene, cyclohexene, and tetrahydropyridine. Fullyunsaturated groups can be aromatic, anti-aromatic, or non-aromatic.Examples of fully unsaturated groups include, but are not limited to,phenyl, cyclooctatetraene, pyridyl, thienyl, and1-methylpyridin-2(1H)-one.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached through an oxygen (“alkoxy”) orsulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl or alkoxy, as the case may be, substituted with oneor more halogen atoms. This term includes perfluorinated alkyl groups,such as —CF₃ and —CF₂CF₃.

The terms “halogen”, “halo”, and “hal” mean F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroarylalkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”. Examples of heteroaryl rings include, butare not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl,1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

It shall be understood that the term “heteroaryl” includes certain typesof heteroaryl rings that exist in equilibrium between two differentforms. More specifically, for example, species such hydropyridine andpyridinone (and likewise hydroxypyrimidine and pyrimidinone) are meantto be encompassed within the definition of “heteroaryl.”

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired functional groups in a compound with multiple reactivesites. In certain embodiments, a protecting group has one or more, orpreferably all, of the following characteristics: a) is addedselectively to a functional group in good yield to give a protectedsubstrate that is b) stable to reactions occurring at one or more of theother reactive sites; and c) is selectively removable in good yield byreagents that do not attack the regenerated, deprotected functionalgroup. As would be understood by one skilled in the art, in some cases,the reagents do not attack other reactive groups in the compound. Inother cases, the reagents may also react with other reactive groups inthe compound. Examples of protecting groups are detailed in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999 (and other editions of thebook), the entire contents of which are hereby incorporated byreference. The term “nitrogen protecting group”, as used herein, refersto an agent used to temporarily block one or more desired nitrogenreactive sites in a multifunctional compound. Preferred nitrogenprotecting groups also possess the characteristics exemplified for aprotecting group above, and certain exemplary nitrogen protecting groupsare also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in“Protective Groups in Organic Synthesis”, Third Edition, John Wiley &Sons, New York: 1999, the entire contents of which are herebyincorporated by reference.

In some embodiments, a methylene unit of an alkyl or aliphatic chain isoptionally replaced with another atom or group. Examples of such atomsor groups include, but are not limited to, nitrogen, oxygen, sulfur,—C(O)—, —C(═N—CN)—, —C(═NR)—, —C(═NOR)—, —SO—, and —SO₂—. These atoms orgroups can be combined to form larger groups. Examples of such largergroups include, but are not limited to, —OC(O)—, —C(O)CO—, —CO₂—,—C(O)NR—, —C(═N—CN), —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—,—OC(O)NR—, and —NRSO₂NR—, wherein R is, for example, H or C₁₋₆aliphatic.It should be understood that these groups can be bonded to the methyleneunits of the aliphatic chain via single, double, or triple bonds. Anexample of an optional replacement (nitrogen atom in this case) that isbonded to the aliphatic chain via a double bond would be —CH₂CH═N—CH₃.In some cases, especially on the terminal end, an optional replacementcan be bonded to the aliphatic group via a triple bond. One example ofthis would be CH₂CH₂CH₂C≡N. It should be understood that in thissituation, the terminal nitrogen is not bonded to another atom.

It should also be understood that, the term “methylene unit” can alsorefer to branched or substituted methylene units. For example, in anisopropyl moiety [—CH(CH₃)₂], a nitrogen atom (e.g. NR) replacing thefirst recited “methylene unit” would result in dimethylamine [—N(CH₃)₂].In instances such as these, one of skill in the art would understandthat the nitrogen atom will not have any additional atoms bonded to it,and the “R” from “NR” would be absent in this case.

Unless otherwise indicated, the optional replacements form a chemicallystable compound. Optional replacements can occur both within the chainand/or at either end of the chain; i.e. both at the point of attachmentand/or also at the terminal end. Two optional replacements can also beadjacent to each other within a chain so long as it results in achemically stable compound. For example, a C₃ aliphatic can beoptionally replaced by 2 nitrogen atoms to form —C—N≡N. The optionalreplacements can also completely replace all of the carbon atoms in achain. For example, a C₃ aliphatic can be optionally replaced by —NR—,—C(O)—, and —NR— to form —NRC(O)NR— (a urea).

Unless otherwise indicated, if the replacement occurs at the terminalend, the replacement atom is bound to a hydrogen atom on the terminalend. For example, if a methylene unit of —CH₂CH₂CH₃ were optionallyreplaced with —O—, the resulting compound could be —OCH₂CH₃, —CH₂OCH₃,or —CH₂CH₂OH. In another example, if a methylene unit of —CH₂CH₂CH₃ wasoptionally replaced with —NH—, the resulting compound could be—NHCH₂CH₃,—CH₂NHCH₃, or —CH₂CH₂NH₂. It should be understood that if the terminalatom does not contain any free valence electrons, then a hydrogen atomis not required at the terminal end (e.g., —CH₂CH₂CH═O or —CH₂CH₂C≡N).

Unless otherwise indicated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, geometric,conformational, and rotational) forms of the structure. For example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers are included inthis invention. As would be understood to one skilled in the art, asubstituent can freely rotate around any rotatable bonds. For example, asubstituent drawn as

also represents

Therefore, single stereochemical isomers as well as enantiomeric,diastereomeric, geometric, conformational, and rotational mixtures ofthe present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

Pharmaceutically Acceptable Salts, Solvates, Chlatrates, Prodrugs andother Derivatives

The compounds described herein can exist in free form, or, whereappropriate, as salts. Those salts that are pharmaceutically acceptableare of particular interest since they are useful in administering thecompounds described below for medical purposes. Salts that are notpharmaceutically acceptable are useful in manufacturing processes, forisolation and purification purposes, and in some instances, for use inseparating stereoisomeric forms of the compounds of the invention orintermediates thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue side effects, such as, toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsdescribed herein include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds.

Where the compound described herein contains a basic group, or asufficiently basic bioisostere, acid addition salts can be preparedby 1) reacting the purified compound in its free-base form with asuitable organic or inorganic acid and 2) isolating the salt thusformed. In practice, acid addition salts might be a more convenient formfor use and use of the salt amounts to use of the free basic form.

Examples of pharmaceutically acceptable, non-toxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like.

Where the compound described herein contains a carboxy group or asufficiently acidic bioisostere, base addition salts can be preparedby 1) reacting the purified compound in its acid form with a suitableorganic or inorganic base and 2) isolating the salt thus formed. Inpractice, use of the base addition salt might be more convenient and useof the salt form inherently amounts to use of the free acid form. Saltsderived from appropriate bases include alkali metal (e.g., sodium,lithium, and potassium), alkaline earth metal (e.g., magnesium andcalcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention alsoenvisions the quaternization of any basic nitrogen-containing groups ofthe compounds disclosed herein. Water or oil-soluble or dispersibleproducts may be obtained by such quaternization.

Basic addition salts include pharmaceutically acceptable metal and aminesalts. Suitable metal salts include the sodium, potassium, calcium,barium, zinc, magnesium, and aluminum. The sodium and potassium saltsare usually preferred. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Suitable inorganic base addition salts are prepared frommetal bases, which include sodium hydride, sodium hydroxide, potassiumhydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide,magnesium hydroxide, zinc hydroxide and the like. Suitable amine baseaddition salts are prepared from amines which are frequently used inmedicinal chemistry because of their low toxicity and acceptability formedical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and thelike are examples of suitable base addition salts.

Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds described herein and theirpharmaceutically acceptable acid or base addition salts.

It should be understood that this invention includesmixtures/combinations of different pharmaceutically acceptable salts andalso mixtures/combinations of compounds in free form andpharmaceutically acceptable salts.

The compounds described herein can also exist as pharmaceuticallyacceptable solvates (e.g., hydrates) and clathrates. As used herein, theterm “pharmaceutically acceptable solvate,” is a solvate formed from theassociation of one or more pharmaceutically acceptable solvent moleculesto one of the compounds described herein. The term solvate includeshydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate,tetrahydrate, and the like).

As used herein, the term “hydrate” means a compound described herein ora salt thereof that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, the term “clathrate” means a compound described hereinor a salt thereof in the form of a crystal lattice that contains spaces(e.g., channels) that have a guest molecule (e.g., a solvent or water)trapped within.

In addition to the compounds described herein, pharmaceuticallyacceptable derivatives or prodrugs of these compounds may also beemployed in compositions to treat or prevent the herein identifieddisorders.

A “pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable ester, salt of an ester, or other derivativeor salt thereof of a compound described herein which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound described herein or an inhibitorily activemetabolite or residue thereof. Particularly favoured derivatives orprodrugs are those that increase the bioavailability of the compoundswhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound described herein. Prodrugs may become active upon such reactionunder biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofthe invention that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of compounds described herein that comprise —NO, —NO₂, —ONO,or —ONO₂ moieties. Prodrugs can typically be prepared using well-knownmethods, such as those described by BURGER'S MEDICINAL CHEMISTRY ANDDRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

ABBREVIATIONS

The following abbreviations are used:

-   DMSO dimethyl sulfoxide-   DCM dichloromethane-   ATP adenosine triphosphate-   ¹HNMR proton nuclear magnetic resonance-   HPLC high performance liquid chromatography-   LCMS liquid chromatography-mass spectrometry-   Rt retention time-   RT room temperature-   TEA triethylamine-   NMP N-methyl-2-pyrrolidone-   TFA trifluoroacetic acid-   Bp boiling point-   DMF dimethylformamide-   PTSA p-Toluenesulfonic acid-   DIPEA N,N-diisopropylethylamine-   mCPBA meta-chloroperoxybenzoic acid-   HOBt hydroxybenzotriazole-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   TBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate-   T3P Propylphosphonic anhydride-   COMU    1-[(1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)]uroniumhexafluorophosphate-   TCTU    [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium    tetrafluoroborate-   HBTU    O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate-   LDA Lithium diisopropylamide-   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide    Compound Uses

One aspect of this invention provides compounds that are inhibitors ofATR kinase, and thus are useful for treating or lessening the severityof a disease, condition, or disorder in a subject or patient where ATRis implicated in the disease, condition, or disorder.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal,and more specifically a human. In one embodiment, the subject is anon-human animal such as a rat or dog. In a preferred embodiment, thesubject is a human.

Another aspect of this invention provides compounds that are useful forthe treatment of diseases, disorders, and conditions characterized byexcessive or abnormal cell proliferation. Such diseases include aproliferative or hyperproliferative disease. Examples of proliferativeand hyperproliferative diseases include, without limitation, cancer andmyeloproliferative disorders.

In some embodiments, said compounds are selected from the groupconsisting of a compound of formula I-A. In another aspect, saidcompounds are selected from the group consisting of formula I-B. Inanother aspect, said compounds are selected from the group consisting offormula I or I-A-1. The term “cancer” includes, but is not limited tothe following cancers. Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:non-small cell, bronchogenic carcinoma (squamous cell or epidermoid,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, larynx,adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or smallintestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi'ssarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), largebowel or large intestines (adenocarcinoma, tubular adenoma, villousadenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum,Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma);Gynecological/Female: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma, undifferentiated thyroid cancer, medullary thyroid carcinoma,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma.

In some embodiments, the cancer is selected from a cancer of the lung orthe pancreas. In other embodiments, the cancer is selected from lungcancer, head and neck cancer, pancreatic cancer, gastric cancer, orbrain cancer. In yet other embodiments, the cancer is selected fromnon-small cell lung cancer, small cell lung cancer, pancreatic cancer,biliary tract cancer, head and neck cancer, bladder cancer, colorectalcancer, glioblastoma, esophageal cancer, breast cancer, hepatocellularcarcinoma, or ovarian cancer.

In some embodiments, the cancer is lung cancer. In other embodiments,the lung cancer is non-small cell lung cancer or small cell lung cancer.In another embodiment, the cancer is non-small cell lung cancer. In yetanother embodiment, the non-small cell lung cancer is squamous non-smallcell lung cancer.

Thus, the term “cancerous cell” as provided herein, includes a cellafflicted by any one of the above-identified conditions. In someembodiments, the cancer is selected from colorectal, thyroid, or breastcancer. In other embodiments, the cancer is triple negative breastcancer.

The term “myeloproliferative disorders”, includes disorders such aspolycythemia vera, thrombocythemia, myeloid metaplasia withmyelofibrosis, hypereosinophilic syndrome, juvenile myelomonocyticleukemia, systemic mast cell disease, and hematopoietic disorders, inparticular, acute-myelogenous leukemia (AML), chronic-myelogenousleukemia (CML), acute-promyelocytic leukemia (APL), and acutelymphocytic leukemia (ALL).

Pharmaceutical Compositions

The present invention also provides compounds and compositions that areuseful as inhibitors of ATR kinase.

One aspect of this invention provides pharmaceutically acceptablecompositions that comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle.

The pharmaceutically acceptable carrier, adjuvant, or vehicle, as usedherein, includes any and all solvents, diluents, or other liquidvehicle, dispersion or suspension aids, surface active agents, isotonicagents, thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Combination Therapies

Another aspect of this invention is directed towards a method oftreating cancer in a subject in need thereof, comprising administrationof a compound of this invention or a pharmaceutically acceptable saltthereof, and an additional therapeutic agent. In some embodiments, saidmethod comprises the sequential or co-administration of the compound ora pharmaceutically acceptable salt thereof, and the additionaltherapeutic agent.

As used herein, the term “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more therapeutic agents). The use of the term does not restrictthe order in which therapies (e.g., therapeutic agents) are administeredto a subject.

In some embodiments, said additional therapeutic agent is an anti-canceragent. In other embodiments, said additional therapeutic agent is aDNA-damaging agent. In yet other embodiments, said additionaltherapeutic agent is selected from radiation therapy, chemotherapy, orother agents typically used in combination with radiation therapy orchemotherapy, such as radiosensitizers and chemosensitizers. In yetother embodiments, said additional therapeutic agent is ionizingradiation.

As would be known by one of skill in the art, radiosensitizers areagents that can be used in combination with radiation therapy.Radiosensitizers work in various different ways, including, but notlimited to, making cancer cells more sensitive to radiation therapy,working in synergy with radiation therapy to provide an improvedsynergistic effect, acting additively with radiation therapy, orprotecting surrounding healthy cells from damage caused by radiationtherapy. Likewise chemosensitizers are agents that can be used incombination with chemotherapy. Similarly, chemosensitizers work invarious different ways, including, but not limited to, making cancercells more sensitive to chemotherapy, working in synergy withchemotherapy to provide an improved synergistic effect, actingadditively to chemotherapy, or protecting surrounding healthy cells fromdamage caused by chemotherapy.

Examples of DNA-damaging agents that may be used in combination withcompounds of this invention include, but are not limited to Platinatingagents, such as Carboplatin, Nedaplatin, Satraplatin and otherderivatives; Topo I inhibitors, such as Topotecan, irinotecan/SN38,rubitecan and other derivatives; Antimetabolites, such as Folic family(Methotrexate, Pemetrexed and relatives); Purine antagonists andPyrimidine antagonists (Thioguanine, Fludarabine, Cladribine,Cytarabine, Gemcitabine, 6-Mercaptopurine, 5-Fluorouracil (5FU) andrelatives); Alkylating agents, such as Nitrogen mustards(Cyclophosphamide, Melphalan, Chlorambucil, mechlorethamine, Ifosfamideand relatives); nitrosoureas (eg Carmustine); Triazenes (Dacarbazine,temozolomide); Alkyl sulphonates (eg Busulfan); Procarbazine andAziridines; Antibiotics, such as Hydroxyurea, Anthracyclines(doxorubicin, daunorubicin, epirubicin and other derivatives);Anthracenediones (Mitoxantrone and relatives); Streptomyces family(Bleomycin, Mitomycin C, actinomycin); and Ultraviolet light.

Other therapies or anticancer agents that may be used in combinationwith the inventive agents of the present invention include surgery,radiotherapy (in but a few examples, gamma-radiation, neutron beamradiotherapy, electron beam radiotherapy, proton therapy, brachytherapy,and systemic radioactive isotopes, to name a few), endocrine therapy,biologic response modifiers (interferons, interleukins, and tumornecrosis factor (TNF) to name a few), hyperthermia and cryotherapy,agents to attenuate any adverse effects (e.g., antiemetics), and otherapproved chemotherapeutic drugs, including, but not limited to, the DNAdamaging agents listed herein, spindle poisons (Vinblastine,Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide,Irinotecan, Topotecan), nitrosoureas (Carmustine, Lomustine), inorganicions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones(Tamoxifen, Leuprolide, Flutamide, and Megestrol), Gleevec™, adriamycin,dexamethasone, and cyclophosphamide.

A compound of the instant invention may also be useful for treatingcancer in combination with any of the following therapeutic agents:abarelix (Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin(Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®);allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®);anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase(Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotenecapsules (Targretin®); bexarotene gel (Targretin®); bleomycin(Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®);busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine(Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®);carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil(Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®);clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®);cyclophosphamide (Cytoxan Injection®); cyclophosphamide (CytoxanTablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®);dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®);daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin(Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin(Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®);doxorubicin liposomal (Doxil®); dromostanolone propionate(Dromostanolone®); dromostanolone propionate (masterone Injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine(Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (ZoladexImplant®); goserelin acetate (Zoladex®); histrelin acetate (HistrelinImplant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®);idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate(Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole(Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase(Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimersodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®);Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®);Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone(Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®);topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®);Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®);tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®);valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); zoledronate (Zometa®) and vorinostat(Zolinza®).

For a comprehensive discussion of updated cancer therapies see,http://www.nci.nih.gov/, a list of the FDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,Seventeenth Ed. 1999, the entire contents of which are herebyincorporated by reference.

Compositions for Administration into a Subject

The ATR kinase inhibitors or pharmaceutical salts thereof may beformulated into pharmaceutical compositions for administration toanimals or humans. These pharmaceutical compositions, which comprise anamount of the ATR inhibitor effective to treat or prevent the diseasesor conditions described herein and a pharmaceutically acceptablecarrier, are another embodiment of the present invention.

The exact amount of compound required for treatment will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the disorder, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

In some embodiments, these compositions optionally further comprise oneor more additional therapeutic agents. For example, chemotherapeuticagents or other anti-proliferative agents may be combined with thecompounds of this invention to treat proliferative diseases and cancer.Examples of known agents with which these compositions can be combinedare listed above under the “Combination Therapies” section and alsothroughout the specification. Some embodiments provide a simultaneous,separate or sequential use of a combined preparation.

Modes of Administration and Dosage Forms

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the disorder being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect. Alternatively, the dosing schedule of the compoundsof the present invention may vary.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient that is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated, the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions. Alternatively, adosage of between 0.01-50 mg/kg body weight/dose of the inhibitor can beadministered to a patient receiving these compounds.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

Administering with Another Agent

Depending upon the particular protein kinase-mediated conditions to betreated or prevented, additional drugs, which are normally administeredto treat or prevent that condition, may be administered together withthe compounds of this invention.

Those additional agents may be administered separately, as part of amultiple dosage regimen, from the protein kinase inhibitor-containingcompound or composition. Alternatively, those agents may be part of asingle dosage form, mixed together with the protein kinase inhibitor ina single composition.

Another aspect of this invention is directed towards a method oftreating cancer in a subject in need thereof, comprising the sequentialor co-administration of a compound of this invention or apharmaceutically acceptable salt thereof, and an anti-cancer agent. Insome embodiments, said anti-cancer agent is selected from Platinatingagents, such as Cisplatin, Oxaliplatin, Carboplatin, Nedaplatin, orSatraplatin and other derivatives; Topo I inhibitors, such asCamptothecin, Topotecan, irinotecan/SN38, rubitecan and otherderivatives; Antimetabolites, such as Folic family (Methotrexate,Pemetrexed and relatives); Purine family (Thioguanine, Fludarabine,Cladribine, 6-Mercaptopurine and relatives); Pyrimidine family(Cytarabine, Gemcitabine, 5-Fluorouracil and relatives); Alkylatingagents, such as Nitrogen mustards (Cyclophosphamide, Melphalan,Chlorambucil, mechlorethamine, Ifosfamide, and relatives); nitrosoureas(e.g. Carmustine); Triazenes (Dacarbazine, temozolomide); Alkylsulphonates (e.g. Busulfan); Procarbazine and Aziridines; Antibiotics,such as Hydroxyurea; Anthracyclines (doxorubicin, daunorubicin,epirubicin and other derivatives); Anthracenediones (Mitoxantrone andrelatives); Streptomyces family (Bleomycin, Mitomycin C, actinomycin)and Ultraviolet light.

Another embodiment provides administering a compound of this inventionwith an additional therapeutic agent that inhibits or modulates a baseexcision repair protein. In some embodiments, the base excision repairprotein is selected from UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG,NEIL1, NEIL2, NEIL3 (DNA glycosylases); APE1, APEX2 (AP endonucleases);LIG1, LIG3 (DNA ligases I and III); XRCC1 (LIG3 accessory); PNK, PNKP(polynucleotide kinase and phosphatase); PARP1, PARP2 (Poly(ADP-Ribose)Polymerases); PolB, PolG (polymerases); FEN1 (endonuclease) orAprataxin. In other embodiments, the base excision repair protein isselected from PARP1, PARP2, or PolB. In yet other embodiments, the baseexcision repair protein is selected from PARP1 or PARP2. In someembodiments, the agent is selected from Olaparib (also known as AZD2281or KU-0059436), Iniparib (also known as BSI-201 or SAR240550), Veliparib(also known as ABT-888), Rucaparib (also known as PF-01367338),CEP-9722, INO-1001, MK-4827, E7016, BMN673, or AZD2461.

Biological Samples

As inhibitors of ATR kinase, the compounds and compositions of thisinvention are also useful in biological samples. One aspect of theinvention relates to inhibiting ATR kinase activity in a biologicalsample, which method comprises contacting said biological sample with acompound described herein or a composition comprising said compound. Theterm “biological sample”, as used herein, means an in vitro or an exvivo sample, including, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof. The term “compounds described herein” includescompounds of formula I, I-A, I-A-1, and I-B.

Inhibition of ATR kinase activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, blood transfusion,organ-transplantation, and biological specimen storage.

Study of Protein Kinases

Another aspect of this invention relates to the study of protein kinasesin biological and pathological phenomena; the study of intracellularsignal transduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the kinase activity or ATPaseactivity of the activated kinase. Alternate in vitro assays quantitatethe ability of the inhibitor to bind to the protein kinase and may bemeasured either by radiolabelling the inhibitor prior to binding,isolating the inhibitor/kinase complex and determining the amount ofradiolabel bound, or by running a competition experiment where newinhibitors are incubated with the kinase bound to known radioligands.Detailed conditions for assaying a compound utilized in this inventionas an inhibitor of ATR is set forth in the Examples below.

Another aspect of the invention provides a method for modulating enzymeactivity by contacting a compound described herein with ATR kinase.

Methods of Treatment

In one aspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder where ATRkinase is implicated in the disease state. In another aspect, thepresent invention provides a method for treating or lessening theseverity of an ATR kinase disease, condition, or disorder whereinhibition of enzymatic activity is implicated in the treatment of thedisease. In another aspect, this invention provides a method fortreating or lessening the severity of a disease, condition, or disorderwith compounds that inhibit enzymatic activity by binding to the ATRkinase. Another aspect provides a method for treating or lessening theseverity of a kinase disease, condition, or disorder by inhibitingenzymatic activity of ATR kinase with an ATR kinase inhibitor.

One aspect of the invention relates to a method of inhibiting ATR kinaseactivity in a patient, which method comprises administering to thepatient a compound described herein, or a composition comprising saidcompound. In some embodiments, said method is used to treat or prevent acondition selected from proliferative and hyperproliferative diseases,such as cancer.

Another aspect of this invention provides a method for treating,preventing, or lessening the severity of proliferative orhyperproliferative diseases comprising administering an effective amountof a compound, or a pharmaceutically acceptable composition comprising acompound, to a subject in need thereof. In some embodiments, said methodis used to treat or prevent cancer. In some embodiments, said method isused to treat or prevent a type of cancer with solid tumors. In yetanother embodiment, said cancer is selected from the following cancers:Oral: buccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: non-small cell,bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Skin:malignant melanoma, basal cell carcinoma, squamous cell carcinoma,Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, keloids, psoriasis, Thyroid gland: papillarythyroid carcinoma, follicular thyroid carcinoma; medullary thyroidcarcinoma, multiple endocrine neoplasia type 2A, multiple endocrineneoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma,paraganglioma; and Adrenal glands: neuroblastoma.

In some embodiments, the cancer is selected from the cancers describedherein. In some embodiments, said cancer is lung cancer, head and neckcancer, pancreatic cancer, gastric cancer, or brain cancer. In otherembodiments, the cancer is selected from a cancer of the lung or thepancreas.

In yet other embodiments, the cancer is selected from non-small celllung cancer, small cell lung cancer, pancreatic cancer, biliary tractcancer, head and neck cancer, bladder cancer, colorectal cancer,glioblastoma, esophageal cancer, breast cancer, hepatocellularcarcinoma, or ovarian cancer.

In some embodiments, the lung cancer is small cell lung cancer and theadditional therapeutic agents are cisplatin and etoposide. In otherexamples, the lung cancer is non-small cell lung cancer and theadditional therapeutic agents are gemcitabine and cisplatin. In yetother embodiments, the non-small cell lung cancer is squamous non-smallcell lung cancer. In another embodiment, the cancer is breast cancer andthe additional therapeutic agent is cisplatin. In other embodiments, thecancer is triple negative breast cancer.

In certain embodiments, an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective inorder to treat said disease. The compounds and compositions, accordingto the method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of said disease.

One aspect provides a method for inhibiting ATR in a patient comprisingadministering a compound described herein as described herein. Anotherembodiment provides a method of treating cancer comprising administeringto a patient a compound described herein, wherein the variables are asdefined herein.

Some embodiments comprising administering to said patient an additionaltherapeutic agent selected from a DNA-damaging agent; wherein saidadditional therapeutic agent is appropriate for the disease beingtreated; and said additional therapeutic agent is administered togetherwith said compound as a single dosage form or separately from saidcompound as part of a multiple dosage form.

In some embodiments, said DNA-damaging agent is selected from ionizingradiation, radiomimetic neocarzinostatin, a platinating agent, a Topo Iinhibitor, a Topo II inhibitor, an antimetabolite, an alkylating agent,an alkyl sulphonates, an antimetabolite, or an antibiotic. In otherembodiments, said DNA-damaging agent is selected from ionizingradiation, a platinating agent, a Topo I inhibitor, a Topo II inhibitor,or an antibiotic.

Examples of Platinating agents include Cisplatin, Oxaliplatin,Carboplatin, Nedaplatin, Satraplatin and other derivatives. Otherplatinating agents include Lobaplatin, and Triplatin. Other platinatingagents include Tetranitrate, Picoplatin, Satraplatin, ProLindac andAroplatin.

Examples of Topo I inhibitor include Camptothecin, Topotecan,irinotecan/SN38, rubitecan and other derivatives. Other Topo Iinhibitors include Belotecan.

Examples of Topo II inhibitors include Etoposide, Daunorubicin,Doxorubicin, Aclarubicin, Epirubicin, Idarubicin, Amrubicin,Pirarubicin, Valrubicin, Zorubicin and Teniposide.

Examples of Antimetabolites include members of the Folic family, Purinefamily (purine antagonists), or Pyrimidine family (pyrimidineantagonists). Examples of the Folic family include methotrexate,pemetrexed and relatives; examples of the Purine family includeThioguanine, Fludarabine, Cladribine, 6-Mercaptopurine, and relatives;examples of the Pyrimidine family include Cytarabine, gemcitabine,5-Fluorouracil (5FU) and relatives.

Some other specific examples of antimetabolites include Aminopterin,Methotrexate, Pemetrexed, Raltitrexed, Pentostatin, Cladribine,Clofarabine, Fludarabine, Thioguanine, Mercaptopurine, Fluorouracil,Capecitabine, Tegafur, Carmofur, Floxuridine, Cytarabine, Gemcitabine,Azacitidine and Hydroxyurea.

Examples of alkylating agents include Nitrogen mustards, Triazenes,alkyl sulphonates, Procarbazine and Aziridines. Examples of Nitrogenmustards include Cyclophosphamide, Melphalan, Chlorambucil andrelatives; examples of nitrosoureas include Carmustine; examples oftriazenes include Dacarbazine and temozolomide; examples of alkylsulphonates include Busulfan.

Other specific examples of alkylating agents include Mechlorethamine,Cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Melphalan,Prednimustine, Bendamustine, Uramustine, Estramustine, Carmustine,Lomustine, Semustine, Fotemustine, Nimustine, Ranimustine, Streptozocin,Busulfan, Mannosulfan, Treosulfan, Carboquone, ThioTEPA, Triaziquone,Triethylenemelamine, Procarbazine, Dacarbazine, Temozolomide,Altretamine, Mitobronitol, Actinomycin, Bleomycin, Mitomycin andPlicamycin.

Examples of antibiotics include Mitomycin, Hydroxyurea; Anthracyclines,Anthracenediones, Streptomyces family. Examples of Anthracyclinesinclude doxorubicin, daunorubicin, epirubicin and other derivatives;examples of Anthracenediones include Mitoxantrone and relatives;examples of Streptomyces family include Bleomycin, Mitomycin C, andactinomycin.

In certain embodiments, said platinating agent is Cisplatin orOxaliplatin; said Topo I inhibitor is Camptothecin; said Topo IIinhibitor is Etoposide; and said antibiotic is Mitomycin. In otherembodiments, said platinating agent is selected from Cisplatin,Oxaliplatin, Carboplatin, Nedaplatin, or Satraplatin; said Topo Iinhibitor is selected from Camptothecin, Topotecan, irinotecan/SN38,rubitecan; said Topo II inhibitor is selected from Etoposide; saidantimetabolite is selected from a member of the Folic Family, the PurineFamily, or the Pyrimidine Family; said alkylating agent is selected fromnitrogen mustards, nitrosoureas, triazenes, alkyl sulfonates,Procarbazine, or aziridines; and said antibiotic is selected fromHydroxyurea, Anthracyclines, Anthracenediones, or Streptomyces family.

In some embodiments, the additional therapeutic agent is ionizingradiation. In other embodiments, the additional therapeutic agent isCisplatin or Carboplatin. In yet other embodiments, the additionaltherapeutic agent is Etoposide. In yet other embodiments, the additionaltherapeutic agent is Temozolomide.

In certain embodiments, the additional therapeutic agent is selectedfrom one or more of the following: Cisplatin, Carboplatin, gemcitabine,Etoposide, Temozolomide, or ionizing radiation.

Another embodiment provides methods for treating pancreatic cancer byadministering a compound described herein in combination with anotherknown pancreatic cancer treatment. One aspect of the invention includesadministering a compound described herein in combination withgemcitabine. In some embodiments, the pancreatic cancer comprises one ofthe following cell lines: PSN-1, MiaPaCa-2 or Panc-1. According toanother aspect, the cancer comprises one of the following primary tumorlines: Panc-M or MRC5.

Another aspect of the invention includes administering a compounddescribed herein in combination with radiation therapy. Yet anotheraspect provides a method of abolishing radiation-induced G2/M checkpointby administering a compound described herein in combination withradiation treatment.

Another aspect provides a method of treating pancreatic cancer byadministering to pancreatic cancer cells a compound described herein incombination with one or more cancer therapies. In some embodiments, thecompound is combined with chemoradiation, chemotherapy, and/or radiationtherapy. As would be understood by one of skill in the art,chemoradiation refers to a treatment regime that includes bothchemotherapy (such as gemcitabine) and radiation. In some embodiments,the chemotherapy is gemcitabine.

Yet another aspect provides a method of increasing the sensitivity ofpancreatic cancer cells to a cancer therapy selected from gemcitabine orradiation therapy by administering a compound described herein incombination with the cancer therapy.

In some embodiments, the cancer therapy is gemcitabine. In otherembodiments, the cancer therapy is radiation therapy. In yet anotherembodiment the cancer therapy is chemoradiation.

Another aspect provides a method of inhibiting phosphorylation of Chk1(Ser 345) in a pancreatic cancer cell comprising administering acompound described herein after treatment with gemcitabine (100 nM)and/or radiation (6 Gy) to a pancreatic cancer cell.

Another aspect provides method of radiosensitizing hypoxic PSN-1,MiaPaCa-2 or PancM tumor cells by administering a compound describedherein to the tumor cell in combination with radiation therapy.

Yet another aspect provides a method of sensitizing hypoxic PSN-1,MiaPaCa-2 or PancM tumor cells by administering a compound describedherein to the tumor cell in combination with gemcitabine.

Another aspect provides a method of sensitizing PSN-1 and MiaPaCa-2tumor cells to chemoradiation by administering a compound describedherein to the tumor cells in combination with chemoradiation.

Another aspect provides a method of disrupting damage-induced cell cyclecheckpoints by administering a compound described herein in combinationwith radiation therapy to a pancreatic cancer cell.

Another aspect provides a method of inhibiting repair of DNA damage byhomologous recombination in a pancreatic cancer cell by administering acompound described herein in combination with one or more of thefollowing treatments: chemoradiation, chemotherapy, and radiationtherapy.

In some embodiments, the chemotherapy is gemcitabine.

Another aspect provides a method of inhibiting repair of DNA damage byhomologous recombination in a pancreatic cancer cell by administering acompound described herein in combination with gemcitabine and radiationtherapy.

In some embodiments, the pancreatic cancer cells are derived from apancreatic cell line selected from PSN-1, MiaPaCa-2 or Panc-1.

In other embodiments, the pancreatic cancer cells are in a cancerpatient.

Another aspect of the invention provides a method of treating non-smallcell lung cancer comprising administering to a patient a compounddescribed herein in combination with one or more of the followingadditional therapeutic agents: Cisplatin or Carboplatin, Etoposide, andionizing radiation. Some embodiments comprise administering to a patienta compound described herein in combination with Cisplatin orCarboplatin, Etoposide, and ionizing radiation. In some embodiments thecombination is Cisplatin, Etoposide, and ionizing radiation. In otherembodiments the combination is Carboplatin, Etoposide, and ionizingradiation.

Another embodiment provides a method of promoting cell death in cancercells comprising administering to a patient a compound described herein,or a composition comprising said compound.

Yet another embodiment provides a method of preventing cell repair ofDNA damage in cancer cells comprising administering to a patient acompound described herein, or a composition comprising said compound.Yet another embodiment provides a method of preventing cell repaircaused by of DNA damage in cancer cells comprising administering to apatient a compound of formula I, or composition comprising saidcompound.

Another embodiment provides a method of sensitizing cells to DNAdamaging agents comprising administering to a patient a compounddescribed herein, or a composition comprising said compound.

In some embodiments, the method is used on a cancer cell having defectsin the ATM signaling cascade. In some embodiments, said defect isaltered expression or activity of one or more of the following: ATM,p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1/BRIT1, CTIP, orSMC1. In other embodiments, said defect is altered expression oractivity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50,NBS1, 53BP1, MDC1 or H2AX. According to another embodiment, the methodis used on a cancer, cancer cell, or cell expressing DNA damagingoncogenes.

In another embodiment, the cell is a cancer cell expressing DNA damagingoncogenes. In some embodiments, said cancer cell has altered expressionor activity of one or more of the following: K-Ras, N-Ras, H-Ras, Raf,Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A and Rb.

According to another embodiment, the method is used on a cancer, cancercell, or cell has a defect in a protein involved in base excision repair(“base excision repair protein”). There are many methods known in theart for determining whether a tumor has a defect in base excisionrepair. For example, sequencing of either the genomic DNA or mRNAproducts of each base excision repair gene (e.g., UNG, PARP1, or LIG1)can be performed on a sample of the tumor to establish whether mutationsexpected to modulate the function or expression of the gene product arepresent (Wang et al., Cancer Research 52:4824 (1992)). In addition tothe mutational inactivation, tumor cells can modulate a DNA repair geneby hypermethylating its promoter region, leading to reduced geneexpression. This is most commonly assessed using methylation-specificpolymerase chain reaction (PCR) to quantify methylation levels on thepromoters of base excision repair genes of interest. Analysis of baseexcision repair gene promoter methylation is available commercially(http://www.sabiosciences.com/dna_methylation_product/HTML/MEAH-421A.html).

Finally, the expression levels of base excision repair genes can beassessed by directly quantifying levels of the mRNA and protein productsof each gene using standard techniques such as quantitative reversetranscriptase-coupled polymerase chain reaction (RT-PCR) andimmunhohistochemistry (IHC), respectively (Shinmura et al.,Carcinogenesis 25: 2311 (2004); Shinmura et al., Journal of Pathology225:414 (2011)).

In some embodiments, the base excision repair protein is UNG, SMUG1,MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylases);APE1, APEX2 (AP endonucleases); LIG1, LIG3 (DNA ligases I and III);XRCC1 (LIG3 accessory); PNK, PNKP (polynucleotide kinase andphosphatase); PARP1, PARP2 (Poly(ADP-Ribose) Polymerases); PolB, PolG(polymerases); FEN1 (endonuclease) or Aprataxin.

In some embodiments, the base excision repair protein is PARP1, PARP2,or PolB. In other embodiments, the base excision repair protein is PARP1or PARP2.

The methods described above (gene sequence, promoter methylation andmRNA expression) may also be used to characterize the status (e.g.,expression or mutation) of other genes or proteins of interesting, suchDNA-damaging oncogenes expressed by a tumor or defects in the ATMsignaling cascade of a cell.

Yet another embodiment provides use of a compound described herein as aradio-sensitizer or a chemo-sensitizer.

Yet other embodiment provides use of a compound of formula I as a singleagent (monotherapy) for treating cancer. In some embodiments, thecompounds of formula I are used for treating patients having cancer witha DNA-damage response (DDR) defect. In other embodiments, said defect isa mutation or loss of ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1,or H2AX.

Compounds and Compositions for Use

One embodiment provides a compound or composition as described hereinfor use as a radio-sensitizer or a chemo-sensitizer. Another embodimentprovides a compound or composition as described herein for use as asingle agent (monotherapy) for treating cancer.

Another embodiment provides a compound or composition as describedherein for treating patients having cancer with a DNA-damage response(DDR) defect. In some embodiments, said defect is a mutation or loss ofATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, or H2AX. In otherembodiments, said defect is a mutation or loss of ATM, p53, CHK2, MRE11,RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1/BRIT1, CTIP, or SMC1.

Another embodiment provides compounds or compositions described hereinfor treating cancer. In some embodiments, the compound or composition isfurther combined with an additional therapeutic agent described herein.In some embodiments, the compound or composition is further combinedwith a DNA damaging agent described herein.

In some embodiments, the cancer has a defect in a pathway describedherein.

Manufacture of Medicaments

One embodiment provides the use of a compound or composition describedherein for the manufacture of a medicament for use as a radio-sensitizeror a chemo-sensitizer. Another embodiment provides the use of a compoundor composition described herein for the manufacture of a medicament forthe manufacture of a medicament for use as a single agent (monotherapy)for treating cancer.

Yet another embodiment provides the use of a compound or compositiondescribed herein for the manufacture of a medicament for the manufactureof a medicament for treating patients having cancer with a DNA-damageresponse (DDR) defect.

In some embodiments, said defect is a mutation or loss of ATM, p53,CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, or H2AX. In other embodiments,said defect is a mutation or loss of ATM, p53, CHK2, MRE11, RAD50, NBS1,53BP1, MDC1, H2AX, MCPH1/BRIT1, CTIP, or SMC1.

Another embodiment provides the use of a compound or compositiondescribed herein for the manufacture of a medicament for treatingcancer. In some embodiments, the compound or composition is combinedwith an additional therapeutic agent, such as a DNA damaging agent,described herein. In another embodiment, the cancer has a defect in apathway described herein.

Experimental Materials and Methods

All commercially available solvents and reagents were used as received.Microwave reactions were carried out using a CEM Discovery microwave.Flash Chromatography, e.g., was carried out on an ISCO© Combiflash®Companion™ system eluting with a 0 to 100% EtOAc/petroleum ethergradient. Other methods known in the art were also utilized to performFlash Chromotography. Samples were applied pre-absorbed on silica. Wherestated, supercritical fluid chromatography (SFC) was performed on aBerger Minigram SFC machine. All ¹H NMR spectra were recorded using aBruker Avance III 500 instrument at 500 MHz. MS samples were analyzed ona Waters SQD mass spectrometer with electrospray ionization operating inpositive and negative ion mode. Samples were introduced into the massspectrometer using chromatography. All final products had a purity ≧95%,unless specified otherwise in the experimental details. HPLC purity wasmeasured on a Waters Acquity UPLC system with a Waters SQD MS instrumentequipped with a Waters UPLC BEH C8 1.7 μm, 2.1×50 mm column and aVanguard BEH C8 1.7 μm, 2.1×5 mm guard column.

As used herein, the term “Rt(min)” refers to the HPLC retention time, inminutes, associated with the compound. Unless otherwise indicated, theHPLC methods utilized to obtain the reported retention times are asdescribed below:

HPLC Method A

-   Instrument: Waters Acquity UPLC-MS;-   Column: Waters UPLC BEH C8 1.7 μm, 2.1×50 mm with Vanguard BEH C8    1.7 μm, 2.1×5 mm guard column;-   Column temperature: 45° C.;-   Mobile Phase A: 10 mM ammonium formate in water:acetonitrile 95:5,    pH 9;-   Mobile Phase B: acetonitrile;-   Detection: 210-400 nm-   Gradient: initial: 2% B, 0-1.15 min: 2% B to 98% B, 1.15-1.35 min:    hold at 98% B, 1.35-1.40 min: 98% B to 2% B, 1.40-1.50 min: hold at    2% B;-   Flow rate: 1.0 mL/minute;    HPLC Method B-   Instrument: Waters Acquity UPLC-MS;-   Column: Waters UPLC BEH C8 1.7 μm, 2.1×50 mm with Vanguard BEH C8    1.7 μm, 2.1×5 mm guard column;-   Column temperature: 45° C.;-   Mobile Phase A: 10 mM ammonium formate in water:acetonitrile 95:5,    pH 9;-   Mobile Phase B: acetonitrile;-   Detection: 210-400 nm;-   Gradient: 0-0.40 min: 2% B, 0.40-4.85 min: 2% B to 98% B, 4.85-4.90    min: 98% B to 2% B, 4.90-5.00 min: hold at 2% B;-   Flow rate: 0.6 mL/minute.

EXAMPLES AND SCHEMES

The compounds of the disclosure may be prepared in light of thespecification using steps generally known to those of ordinary skill inthe art. Those compounds may be analyzed by known methods, including butnot limited to LCMS (liquid chromatography mass spectrometry) and NMR(nuclear magnetic resonance). The following generic schemes and examplesillustrate how to prepare the compounds of the present disclosure. Theexamples are for the purpose of illustration only and are not to beconstrued as limiting the scope of the invention in any way.

It will be understood that when an inconsistency exists between thechemical structure and the corresponding name provided herein, thechemical structure will control.

Compounds of this invention can be synthesised according to methodssimilar to the one depicted in Scheme 1.

The anion of commercially available allyl cyanoacetate 1 can react withtrichloroacetonitrile to provide intermediate 2. In the anioncondensation step, the anion of commercially available allylcyanoacetate 1 can be generated with a base such as potassium acetate inan appropriate solvent such as an alcohol (e.g., isopropylalcohol). Theanion then reacts with trichloroacetonitrile at room temperature(specific details are given in Preparation 1, Step 1 below).

Intermediate 2 then reacts with hydrazine to form the diaminopyrazole 3.In the pyrazole formation step, intermediate 2 is reacted with hydrazine(or its hydrate) in an aprotic solvent, such as DMF, to provide thediaminopyrazole 3. The reaction occurs under basic conditions (e.g., inthe presence of potassium acetate or AcONa) with heating (e.g., 110° C.)to ensure complete cyclisation (specific details are given inPreparation 1, Step 2 below).

Intermediate 3 can further be condensed with a dielectrophilic couplingpartner to form the pyrimidine 4a-c. In the pyrimidine formation step,intermediate 3 is reacted with a 1,3-dielectrophilic species (e.g., a1,3-dialdehyde or a 3-(dialkylamino)-prop-2-enal) in various types ofsolvents (e.g., DMF or DMSO/water) to furnish the bicyclic cores 4a-c.When one or two of the electrophilic centers is protected/masked (e.g.,aldehyde masked as a ketal), introduction of a sulfonic acid (e.g.,PTSA) is required to liberate the reactive functional group (specificdetails are given in Preparation 4, Step 1 below).

Deprotection, e.g, via hydrolysis, of the allyl ester leads to thecarboxylic acids 5a-c. In the deprotection step, compound 4a-c issubjected to hydrolytic conditions that are known to those skilled inthe art. For example, treatment of 4a-c with phenylsilane or4-methylbenzenesulfinate in the presence of a catalytic amount ofpalladium (e.g., Pd(PPh₃)₄) leads to the formation of the correspondingcarboxylic acid 5a-c. Alternatively, compounds 4a-c could be treatedwith aqueous alkali (e.g., NaOH, KOH) to produce acids 5a-c (specificdetails are given in Preparation 4, Step 2 below).

In the activated ester formation step, the carboxylic acids 5a-c arereacted with amide coupling agents known to those skilled in the art.When the coupling agent is chosen appropriately, the reactions canproceed rapidly (˜1 h) at room temperature in the presence of an organicbase (e.g., triethylamine, DIPEA) to provide the activated esters 6a-c.For example, when the amide coupling agents TBTU [J=H] or TCTU [J=Cl]are used, compounds 6a-c are obtained readily by filtration of thereaction mixture (specific details are given in Preparation 4, Step 3below).

Formation of the activated esters 6a-c prior to the amide bond formationto prepare I-A is generally preferred, although a direct conversion of5a-c into the compounds of formula I-A of this invention is alsopossible. Alternative activated esters can also be utilised (isolated orformed in situ) and will be known to those skilled in the art (e.g.,using TBTU, TCTU, HATU, T3P, COMU coupling agents).

In the amide bond formation step, activated esters 6a-c can react with asubstituted 3-aminopyridine to provide compounds of formula I-A of thisinvention. The reaction conditions for the amide coupling are generallyin an aprotic solvent (e.g., NMP, pyridine, DMF, etc . . . ) withheating (e.g., ≧90° C.) (specific details are given in Example 1 below).The 3-aminopyridine may be further functionalized following amide bondformation.

Alternatively, the two steps described above can be combined: carboxylicacids 5a-c can be used as starting points for the amide bond formation,the activated esters being generated in situ, using the same amidecouplings agents as those described above. Compounds I-A of thisinvention are isolated in a similar manner to the one described above(specific details are given in Example 3a below).

Compounds of formula I, I-A-1, and I-B can also be prepared usingsimilar methods.

Alternatively, compounds of the present disclosure can be preparedaccording to methods similar to the one depicted in Scheme 2.

The amide 8 can readily be prepared from commercially availablecyanoacetic acid 7. In the amide bond formation step, cyanoacetic acid 7can react with a substituted 3-aminopyridine to provide compounds 8 ofthis invention. The reaction conditions for the amide coupling aregenerally in an aprotic solvent (e.g., DCM, NMP, DMF, etc), in thepresence of an organic base, such as an aliphatic amine, (e.g.,triethylamine or DIPEA) and an amide coupling agent known to thoseskilled in the art: for example EDCI, TBTU, COMU, T3P, etc (specificdetails are given in Example 3e, step 1 below).

In the pyrazole formation step, the anion of cyanoamide 8 can begenerated with a base (such as potassium or sodium acetate) in anappropriate solvent such as an alcohol (e.g., ethanol). The anion thenreacts with trichloroacetonitrile at room temperature (specific detailsare given in Example 3e, step 2 below). The resulting solid, which canbe collected by filtration, is then reacted with hydrazine (or itshydrate) in an aprotic solvent, such as DMF or NMP, to provide thediaminopyrazole 9, the latter being further condensed with adielectrophilic coupling partner to form the pyrimidine portion of thecompounds of formula I-A of this invention.

In the pyrimidine formation step, intermediate 9 is reacted with a1,3-dielectrophilic species (e.g., a 1,3-dialdehyde or a3-(dialkylamino)-prop-2-enal) in various types of solvents (e.g.,iPrOH/water, DMF, or DMSO/water) to furnish the desired products I-A.When one or two of the electrophilic centers is protected/masked (e.g.,aldehyde masked as a ketal), introduction of a sulfonic acid (e.g.,PTSA) is required to liberate the reactive functional group. (specificdetails are given in Example 3e, step 3 below).

Compounds of formula I, I-A-1, and I-B can also be prepared usingsimilar methods.

Preparation 1 Allyl 3,5-diamino-1H-pyrazole-4-carboxylate

Step 1: allyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate 2

To a solution of KOAc (589.4 g, 6.006 mol) in isopropanol (3 L) wasadded allyl cyanoacetate (429.4 g, 403.2 mL, 3.432 mol) and the reactionmixture was cooled to 5° C. Trichloroacetonitrile (495.5 g, 3.432 mol)was added in 50 mL portions, maintaining temperature below 15° C. Thereaction mixture was then allowed to warm to 20° C. and stirred for 3 h.Water (˜4 L) was added to dissolve the inorganic materials andprecipitate out the desired product. The mixture was stirred for 20minutes and the solid was isolated by filtration under vacuum. Thissolid was filtered, washed with water (2×0.5 L) and dried in a vacuumoven overnight at 40° C. to afford allyl3-amino-4,4,4-trichloro-2-cyanobut-2-enoate 2 as an off-white powder(787 g, 85%).

Step 2: Allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3

To a suspension of allyl 3-amino-4,4,4-trichloro-2-cyano-but-2-enoate 2(619 g, 2.297 mol) and KOAc (676.3 g, 6.891 mol) in DMF (2.476 L) at 0°C. was slowly added hydrazine hydrate (172.5 g, 167.6 mL, 3.446 mol)over 15 min. The reaction mixture was then stirred at ambienttemperature for 2 h, at which stage ¹H NMR shows complete consumption ofthe starting material. Reaction mixture was then heated overnight at110° C. before being allowed to cool to ambient and stirred for another48 h. The mixture was filtered through a sintered glass funnel to removethe precipitated solid and the filtrate was evaporated under reducedpressure to give a thick liquid. DCM (approx 2 L) was added, and themixture filtered again to remove additional solids that haveprecipitated. The filtrate was purified through a 1 kg silica gel plug(gradient of DCM/MeOH as an eluent), and the solvent was removed toafford an orange solid which was suspended in acetonitrile and heated atabout 70° C. until all the solid went into solution, at which point thesolution was allowed to cool to ambient temperature, then to 2° C. Theprecipitate that formed was isolated by filtration under vacuum, washedwith chilled MeCN (˜50 mL) and dried to constant mass in a vacuum ovento furnish the title compound as an off-white powder (171.2 g, 41%).

Preparation 2a 1H-benzo[d][1,2,3]triazol-1-yl2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate

Step 1: allyl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate4a

To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (42.72g, 234.5 mmol) in DMSO (270.8 mL)/Water (270.8 mL), was added p-TsOHhydrate (46.72 g, 245.6 mmol) and3-(diisopropylamino)-2-fluoro-prop-2-enal (described in TetrahedronLetters, 33(3), 357-60; 1992) (38.69 g, 223.3 mmol). The reactionmixture was heated to 100° C. for 3 h during which time a solid slowlyprecipitated out of solution. The orange suspension was allowed to cooldown to RT overnight. The solid was filtered, washed with water anddried under vacuum to give allyl2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4a as a sandsolid (45.05 g, 85% yield).

Step 2: 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a

To a suspension of allyl2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4a (45 g, 190.5mmol) in DCM (1.35 L) was added phenylsilane (41.23 g, 46.96 mL, 381.0mmol), followed by Pd(PPh₃)₄ (8.805 g, 7.620 mmol). The reaction wasstirred at room temperature for 2 h 30 min. The reaction mixture wasfiltered and the solid was washed with DCM to give a light yellow solid(43.2 g). This solid was triturated further in DCM (225 mL) at RT for 45min, then filtered and dried overnight under vacuum to provide2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a as alight yellow solid (37.77 g, 100% yield).

In an alternative method, 4-methylbenzenesulfinate (anhydrous, 1.2 eqv,22.6 g, 127 mmol) was suspended in dry DMSO (20 vol, 500 ml). Thestirred mixture was warmed to 30° C. under a nitrogen atmosphere. Uponcomplete dissolution Pd(PPh₃)₄ (2 mol %, 2.4 g, 2.1 mmol) was added. Themixture was stirred for 10 min at 25-30° C. after which time a turbidyellow solution was present. Allyl2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate (25 g, 105.8mmol) was added portionwise, maintaining the temperature at 25-30° C.Once addition was complete the cloudy solution was stirred until thereaction was complete by HPLC (2-3 hrs). A heavy precipitate formedafter 15 minutes post addition of the substrate. The mixture becamethicker as the reaction proceeded. The reaction mixture was diluted withwater (125 ml) and 2M HCl (66 ml) was added slowly, maintaining thetemperature at 25-30° C. The slurry was stirred for 30 minutes, thenfiltered. The filtration was slow (2 hrs). The resulting solid waswashed with water, then dried on the sinter. The solid was slurried inDCM (8 vol) for 1 hr. The solid was filtered (rapid filtration) andwashed with DCM. The solid was re-slurried in chloroform (8 vol) for 1hr. The acid was filtered and dried on the sinter. It was further driedin a vacuum oven at 50° C. for 24 hrs. The product was obtained as anoff-white solid (18.6 g, 85%); 1H NMR (500 MHz, DMSO-d6) δ 12.14 (1H,brs), 9.31 (1H, dd), 8.69 (1H, m), 6.47 (2H, brS); 19F NMR (500 MHz,DMSO-d6) δ −153.65; MS (ES+) 197.1.

Step 3: 1H-benzo[d][1,2,3]triazol-1-yl2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate 6a

To a suspension of2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (20 g,102.0 mmol) in chloroform (300 mL) was added Et₃N (11.35 g, 15.63 mL,112.2 mmol). The suspension was stirred for ˜5 mins and then(benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium BoronTetrafluoride was added (32.75 g, 102.0 mmol). The suspension was heatedto 60° C. for 1 h before the thick suspension was allowed to cool downto RT. The resulting suspension was filtered, washed with chloroform(200 mL) and dried under vacuum overnight to afford the title compound6a as a light yellow powder (32.5 g, 88%).

Preparation 2b(6-chlorobenzotriazol-1-yl)-2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate6a*

In a 2.5 L three-necked flask equipped with stirrer bar, condenser,nitrogen line and Hanna temperature probe was charged2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (60 g,305.9 mmol), chloroform (900.0 mL) and triethylamine (32.44 g, 44.68 mL,320.6 mmol).[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium(Boron Tetrafluoride Ion (1)) (87.00 g, 244.7 mmol) was addedportionwise over 5 mins (internal dropped from 22.7 to 21.5° C. oncomplete addition). Mixture heated at 60° C. (internal temp) for 2 h,still a cream suspension. Mixture cooled to room temperature then solidcollected by filtration, washed well with chloroform (until filtrateruns essentially colourless) and dried by suction to leave product 6a*as a cream solid (82.2 g, 77% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.55(dd, 1H), 8.91 (d, 1H), 8.22 (dd, 1H), 8.09 (dd, 1H), 7.57 (dd, 1H) and6.87 (s, 2H). MS (ES+) 348.1.

In an alternative method,2-Amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (30 g,153 mmol) was slurried in acetonitrile (540 ml). Triethylamine (22.5 ml,153 mmol) was added, followed by[(6-chlorobenzotriazol-1yl)oxy-(dimethylamino)methylene]-dimethylammoniumtetrafluoroborate (TCTU, 54.4 g, 153 mmol). The mixture was stirred atroom temperature for 2 hrs. The product was isolated by filtration—thefilter cake was washed with acetonitrile (2×60 ml) (49.3 g, 93%); ¹H NMR(500 MHz, DMSO-d₆) δ 9.55 (dd, 1H), 8.91 (d, 1H), 8.22 (dd, 1H), 8.09(dd, 1H), 7.57 (dd, 1H) and 6.87 (s, 2H); 19F NMR (500 MHz, DMSO-d6) δ−150.1; MS (ES+) 348.1.

Preparation 3 1H-benzo[d][1,2,3]triazol-1-yl2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate

Step 1: 2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4b

To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (1 g,5.489 mmol) in DMF (5 mL) was added(Z)-2-chloro-3-dimethylamino-prop-2-enylidene]-dimethyl-ammoniumhexafluorophosphate (1.683 g, 5.489 mmol), followed by triethylamine(722.1 mg, 994.6 μL, 7.136 mmol). The reaction mixture was heated to 60°C. for 4 h during which time a solid slowly precipitated out ofsolution. The brown suspension was allowed to cool down to RT. The solidwas filtered, washed with water and dried under vacuum to give allyl2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4b as a brownsolid (1.092 g, 72% yield).

Step 2: 2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5b

To a suspension of allyl2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4b (1 g, 3.96mmol) in DCM (15 mL) was added phenylsilane (856.6 mg, 0.9756 mL, 7.916mmol), followed by Pd(PPh₃)₄ (182.9 mg, 0.1583 mmol). The reaction wasstirred at room temperature for 7 h. The reaction mixture was filteredand the solid was washed with DCM to give a light yellow solid (43.2 g).This solid was triturated further in DCM (225 mL) at RT for 45 min, thenfiltered and dried overnight under vacuum to provide2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5b as ayellow solid (791 m, 94% yield).

Step 3: 1H-benzo[d][1,2,3]triazol-1-yl2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate 6b

To a solution of 2-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid 5b (1.51 g, 7.103 mmol) in chloroform (15.1 mL) was added TBTUboron tetrafluoride (2.737 g, 8.524 mmol) and TEA (862.5 mg, 1.188 mL,8.524 mmol). The reaction mixture was stirred at 50° C. for one hour.The resulting suspension was filtered, and the solid triturated in ethylacetate to afford the title compound 6b as a yellow solid (2.05 g, 88%).

Preparation 4 1H-benzo[d][1,2,3]triazol-1-yl2-amino-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

Step 1: allyl2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c

To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (63.49g, 348.5 mmol) in a mixture of DMSO (340 mL) and water (340 mL), wasadded 3-(dimethoxymethyl)-4,4-dimethoxy-butanenitrile (Scheme 3, below)(85 g, 418.2 mmol), followed by para-toluene Sulfonic acid hydrate (1)(11.27 g, 59.24 mmol). The reaction mixture was heated to 85° C. andstirred overnight. The reaction mixture was cooled with an ice bath. Themixture was diluted with EtOAc (680 mL) and a saturated aqueous solutionof NaHCO₃ (1.36 L). The precipitate was filtered and rinsed with water,then with a mixture of water and EtOAc. The brown solid was dried undervacuum to give allyl2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c as abrown solid (55.94 g, 62% yield).

Step 2: 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid 5c

To a suspension of allyl2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c (10.2g, 39.65 mmol) in DCM (350 mL) was added phenylsilane (8.581 g, 9.773mL, 79.3 mmol), followed by Pd(PPh₃)₄ (1.5 g, 1.298 mmol). The reactionwas stirred at room temperature for 2 h. The reaction mixture wasfiltered and the solid was washed with DCM and dried under vacuum toprovide 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid 5c as a yellow solid (8.61 g, 100% yield).

Step 3: 1H-benzo[d][1,2,3]triazol-1-yl2-amino-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 6c

To a solution of2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5c(5.11 g, 23.53 mmol) in DCM (51 mL) was added TBTU boron tetrafluoride(9.067 g, 28.24 mmol) and TEA (2.858 g, 3.937 mL, 28.24 mmol). Thereaction mixture was stirred at room temperature for one hour. Theresulting suspension was filtered, and the solid triturated in hotchloroform to afford the title compound 6c as a beige solid (6.59 g,84%).

Example 12-amino-6-fluoro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-1)

To a suspension of benzotriazol-1-yl2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (preparedaccording to methods similar to the one depicted in Preparation 2a) (5g, 15.62 mmol) in NMP (78.27 mL) was added4-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-3-amine (prepared according tomethods similar to the one depicted in Preparation N-1, described below)(3.660 g, 15.62 mmol) and the resulting mixture heated at 100° C. for 18hours. The reaction mixture was cooled to RT and then passed through apre-wetted SCX cartridge (2×50 g cartridge) and the cartridge was washedwith methanol. The product was eluted with 2M ammonia in methanol andthe eluent was concentrated in vacuo to leave a dark solid that waspurified by column chromatography on silica using the ISCO columncompanion, eluting with DCM and 90:10:1 DCM:MeOH:NH₃ (0-100% gradient,40 g column). Product fractions were combined and concentrated in vacuoto leave the product as a yellow solid which was then recrystallisedfrom methanol to leave pure product as a yellow solid. MS (ES+) 413.2.

Example 22-amino-N-(4-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-2)

To a solution of tert-butylN-[1-[3-[[2-amino-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-4-pyridyl]-4-piperidyl]carbamateprepared according to a method similar to the one described in Example 1(70 mg, 0.1424 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol) andthe mixture was stirred at ambient temperature for 1.5 hours. Thereaction mixture was evaporated to dryness and purified by HPLC: 10-90%ACN in Water (TFA modifier) and the fractions were freeze-dried. Thesolid residue was dissolved in methanol (1 mL) and loaded onto apre-wetted (15 mL methanol) 2 g SCX-2 cartridge. The cartridge waswashed with methanol (2×15 mL) then the product eluted as a free baseusing 2M ammonia in methanol solution (3×15 mL). The product-containingfractions were evaporated to dryness, re-dissolved in water/methanol andfreeze-dried to afford the desired product as a yellow solid (17 mg,31%). MS (ES+) 391.1.

Example 3a2-amino-6-fluoro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-3)

A mixture of 4-(4-methylpiperazin-1-yl)pyridin-3-amine (preparedaccording to methods similar to the one depicted in Preparation N-1,described below) (588.1 mg, 3.059 mmol),2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a(prepared according to methods similar to the ones depicted in thesequence Step 1-Step 2 of Preparation 2a) (500 mg, 2.549 mmol), TBTU(1.146 g, 3.569 mmol) and Et₃N (515.9 mg, 710.6 μL, 5.098 mmol) in NMP(7 mL) was stirred at 110° C. in a sealed tube, for 20 h. The reactionmixture was diluted with EtOAc, washed with a saturated bicarbonateaqueous solution and brine. The organic was dried over MgSO₄ andconcentrated after filtration. The solid was triturated in DCM and thenfiltered off. It was further purified by Fractionlynx HPLC to yield thetitle compound as a colourless solid. MS (ES+) 371.3.

Alternatively, compound I-N-3 can be prepared according to Scheme 2using the procedure described in Example 3b.

Example 3b2-amino-6-fluoro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-3) Step 1:2-cyano-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)acetamide 8

To an ice cold solution of 2-cyanoacetic acid 7 (1.15 g, 13.52 mmol) inDCM (40 mL) was added oxalyl chloride (1.3 mL, 14.90 mmol) dropwise,followed by a catalytic amount of DMF. The reaction mixture was stirredat room temperature for 3 h and then concentrated in vacuo to removesolvent. The residue was added to a solution of4-(4-methylpiperazin-1-yl)pyridin-3-amine (Prepared according to methodssimilar to the one depicted in Preparation N-1, described below) (1.3 g,6.762 mmol) and Et₃N (1.026 g, 1.413 mL, 10.14 mmol) in THF (40 mL) andthe reaction mixture was stirred at room temperature for 18 h. Themixture was diluted with EtOAc, washed with a saturated bicarbonateaqueous solution and brine. The aqueous layer was further extracted withDCM (20 mL×2). The combined organic layers were dried over Na₂SO₄ andconcentrated to give2-cyano-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)acetamide 8 as ayellow oil. MS (ES+) 260.1.

Step 2:3,5-diamino-N-[4-(4-methylpiperazin-1-yl)-3-pyridyl]-1H-pyrazole-4-carboxamide9

To a suspension of2-cyano-N-[4-(4-methylpiperazin-1-yl)-3-pyridyl]acetamide 8 (1.6 g,6.170 mmol) in ethanol (40 mL) was added sodium acetate (1.052 g, 12.83mmol), followed by trichloroacetonitrile (1.042 g, 733.8 μL, 7.219 mmol)dropwise. The heterogeneous mixture was stirred at room temperatureunder an atmosphere of nitrogen for 18 h. The reaction mixture wasconcentrated under vacuum, and the residue was dissolved in NMP (30 mL).Hydrazine hydrate (803 mg, 780.4 μL, 16.04 mmol) was added and thereaction mixture was stirred at room temperature for 3 h. The solventswere removed under vacuum and the residue triturated in DCM to form abrown solid which was isolated by filtration to provide3,5-diamino-N-[4-(4-methylpiperazin-1-yl)-3-pyridyl]-1H-pyrazole-4-carboxamide9 (1 g, 51%). MS (ES+) 317.1.

Step 3:2-amino-6-fluoro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (Z)-3-(diisopropylamino)-2-fluoro-prop-2-enal (TetrahedronLetters (1992), 33(3), 357-60) (22.81 mg, 0.1317 mmol),4-methylbenzenesulfonic acid (Water (1)) (30.05 mg, 0.1580 mmol),3,5-diamino-N-[4-(4-methylpiperazin-1-yl)-3-pyridyl]-1H-pyrazole-4-carboxamide(50 mg, 0.1580 mmol) in DMSO (1 mL)/H₂O (0.5 mL) was stirred at 140° C.for 25 min. The crude mixture was purified by Fractionlynx HPLC. Theaqueous fractions were combined and lyophilised to yield2-amino-6-fluoro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.(10 mg, 21%).

Example 3c2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-G-4)

A suspension of benzotriazol-1-yl2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (6.271 g,20.02 mmol),[1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanonehydrobromide 17a (6.98 g, 16.68 mmol) and DIPEA (2.802 g, 3.776 mL,21.68 mmol) in pyridine (63 mL) were placed in a sealed tube and heatedat 100° C. for 24 h. The mixture cooled to room temperature thenconcentrated in vacuo. The resulting solid was loaded onto silica andpurified by chromatography (330 g SiO₂, 0.5-7.5% MeOH (containing 10%ammonium hydroxide)/DCM). The residue was stirred in ethanol for 5 minsand the solid that formed was collected by filtration, washed withminimal ethanol, dried by suction for 2 h, affording desired product asa pale yellow solid (4.71 g, 56.5%). MS (ES+) 500.2; ¹H NMR (DMSO-d6) δ10.63 (s, 1H), 9.67 (s, 1H), 9.47 (dd, J=4.8, 2.5 Hz, 1H), 9.25 (dd,J=2.6, 0.7 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 6.79 (s, 2H), 3.60 (t, J=5.0Hz, 2H), 3.55 (t, J=4.9 Hz, 2H), 3.19 (m, 2H), 3.03 (m, 2H), 2.95 (tt,J=11.7, 3.6 Hz, 1H), 2.34 (t, J=5.0 Hz, 2H), 2.29 (t, J=5.1 Hz, 2H),2.20 (s, 3H), 2.13 (qd, J=12.4, 3.9 Hz, 2H), 1.75-1.72 (m, 2H).

Example 3d2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-G-4)

In an alternative method to the the one reported in Example 3c, compoundI-G-4 can be prepared as follows:

A 2 L flask equipped with an overhead stirrer, an air condenser, athermometer and a nitrogen line was charged with2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (14.19g, 72.36 mmol), then pyridine (353 mL) followed by[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammoniumtrifluoroborate (22.14 g, 65.78 mmol), with stirring at ambienttemperature. The suspension was heated at 50° C. over 1 h period. DIPEA(17.85 g, 24.06 mL, 138.1 mmol) was then added, followed by[1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanonehydrochloride 17b (prepared according to Preparation N-14) (23.54 g,65.78 mmol). The internal temperature was raised to 90° C. and thereaction mixture stirred at this temperature for 13 h. The mixture wasthen allowed to cool slowly and the solvent was evaporated in vacuo. Theresidue was slurried in DCM (250 ml) and the orange solid waspartitioned between DCM (1 L) and 2M sodium carbonate (200 mL). Theorganic layer was separated, washed with 2M sodium carbonate (200 mL),dried (MgSO₄), filtered and concentrated in vacuo to leave an orangesolid. This solid residue was further slurried in EtOH (115 mL) for 10mins then collected by filtration, washed with further ethanol (approx100 mL) dried by suction to afford product as a pale yellow solid, 18.75g, 57%).

Example 3e2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-G-4)

In an alternative method to the the ones reported in Example 3c and 3d,compound I-G-4 can be prepared as follows:

Step 1:2-cyano-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)acetamide8a

To a solution of[1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanonehydrochloride 17b (300 mg, 0.8383 mmol) and DIPEA (541.8 mg, 730.2 μL,4.192 mmol) in DCM (8 mL) was added cyanoacetic acid 7 (106.9 mg, 1.257mmol). The reaction mixture was cooled on an ice bath and EDCI (241.0mg, 1.257 mmol) was then added. The mixture was stirred at roomtemperature overnight, then heated under reflux for 4 h. The reactionmixture was cooled to room temperature and diluted with DCM (30 mL),washed with water (2×10 ml), then saturated sodium hydrogen carbonatesolution (10 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo to afford the desired product 8a as an orange foam(292 mg, 90%). MS (ES+) 389.2.

Step 2:3,5-diamino-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1H-pyrazole-4-carboxamide9a

2-Cyano-N-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]acetamide8a (290 mg, 0.7466 mmol) was slurried in ethanol (3.3 mL). Sodiumacetate (127.4 mg, 1.553 mmol) was added, followed bytrichloroacetonitrile (129.4 mg, 91.13 μL, 0.8959 mmol) and the reactionmixture was stirred at room temperature for 1 hr, after which time anoff-white precipitate had formed. The solid was collected by filtration,washed with minimal ethanol then minimal water and dried by suction togive a white solid (155 mg). The filtrate was concentrated in vacuo toremove ethanol then residual aqueous solution was extracted with EtOAc(3×). The combined organic layers was dried (MgSO₄), filtered andconcentrated to dryness in vacuo to leave a viscous oil which wastriturated in EtOAc (5 mL) to form an off white precipitate that wascollected by filtration, washed with minimal EtOAc and dried by suctionto leave a second crop of solid (49 mg). A total of 204 mg (51%) of3-amino-4,4,4-trichloro-2-cyano-N-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]but-2-enamidewas isolated; MS (ES+) 532.0.

3-Amino-4,4,4-trichloro-2-cyano-N-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]but-2-enamide(4.1 g, 7.695 mmol) was dissolved in N-methylpyrrolidinone (40 mL).Hydrazine hydrate (1.002 g, 973.8 μL, 20.01 mmol) was added and thereaction mixture was stirred at room temperature for 10 mins, thenheated at 80° C. for 3.5 h. The mixture was concentrated in vacuo andthe residue was then partitioned between EtOAc/water. The organicorganic layer was washed with water (2×), brine (1×), dried (MgSO4),filtered and concentrated in vacuo to provide the desired compound as awhite solid. (64%). MS (ES+) 446.1, ¹H NMR (500 MHz, DMSO) 11.03 (s,1H), 9.45 (s, 1H), 8.69 (s, 1H), 8.52 (d, J=4.7 Hz, 1H), 7.36 (br s,4H), 4.47-4.43 (m, 1H), 4.23-4.21 (m, 1H), 3.50-3.47 (m, 2H), 3.41-3.39(m, 2H), 3.24-3.15 (m, 2H) 3.05-2.98 (m, 2H), 2.93-2.88 (m, 2H),2.77-2.76 (m, 4H), 1.73-1.71 (m, 4H).

Step 3:2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideI-G-4

To a suspension of3,5-diamino-N-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]-1H-pyrazole-4-carboxamide9a (106 mg, 1.19 mmol) in IPA/water (1:1, 1 mL) and acetic acid (71.46mg, 67.67 μL, 0.1078 mmol) was added3-(diisopropylamino)-2-fluoro-prop-2-enal (41.21 mg, 0.2379 mmol). Thereaction mixture was heated under reflux for 6 h and was then allowed tocool to room temperature overnight. IPA was removed in vacuo, and theresulting aqueous solution was partitioned between DCM and 2M sodiumcarbonate solution. The organic layer was washed with 1:1 brine/water,dried (MgSO₄) filtered and concentrated in vacuo to leave a yellow solidwhich was stirred as a suspension in ethanol (0.5 mL) for 2 h. The solidwas collected by filtration to give the desired compound I-G-4 (63 mg,53%).

Example 3f2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3-yl)piperazine-1-carbonyl]-1-piperidyl]-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-G-32)

Step 1: tert-butyl1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylate28

A mixture of (6-chlorobenzotriazol-1-yl)2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (44.02 g,126.6 mmol) and tert-butyl1-(3-amino-5-fluoro-4-pyridyl)piperidine-4-carboxylate 27 (preparedaccording to Preparation N-15) (34 g, 115.1 mmol) in pyridine (510.0 mL)was heated at 95° C. internally overnight (18 h). Mixture was cooled toroom temperature (product precipitated) then added ethanol (340.0 mL)and stirred at room temperature for 10 mins. Collected yellow solid byfiltration, washed well with ethanol, dried by suction, then on high vacline for 1 h to leave product 28 as a yellow solid, (32.5 g 56% yield).¹H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H),8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15-2.93 (m, 4H), 2.55-2.47(masked signal, 1H), 2.02-1.91 (m, 4H), 1.47 (s, 9H). MS (ES+) 474.2.

Step 2:1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylicacid trifluorocetate 29

To a suspension of tert-butyl1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylate28 (69.7 g, 147.2 mmol) in DCM (348.5 mL) and triethylsilane (18.83 g,25.87 mL, 161.9 mmol) was added TFA (151.1 g, 102.1 mL, 1.325 mol)(mixture sets solid on initial addition of TFA then goes into solutionafter complete addition). Resulting orange solution was stirred at roomtemperature overnight. Additional TFA (16.78 g, 11.34 mL, 147.2 mmol)was added and the mixture stirred at room temperature for 2 h. Mixturethen heated at 40° C. for 20 mins to force reaction to completion.Mixture was concentrated in vacuo, chloroform (300 mL) was added andmixture again concentrated in vacuo to leave an orange solid suspension.Mixture triturated in DCM (approx. 200 mL), stirred for 20 mins thensolid collected by filtration, washed with minimal DCM and dried bysuction to leave a yellow solid. Filtrate was concentrated in vacuo,residue re-slurried in DCM (approx 50 mL), stirred for 20 mins thensolid collected by filtration, washed with minimal DCM and dried bysuction to leave a yellow solid which was combined with first crop ofsolid. Solid dried under vacuum overnight to leave desired product 29 asa yellow solid (82.8 g, 96%). ¹H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H),9.59 (s, 1H), 9.50 (dd, 1H), 8.84 (dd, 1H), 8.33 (d, 1H), 3.13-3.10 (m,4H), 2.57-2.47 (masked signal, 1H) and 2.08-1.93 (m, 4H). MS (ES+)418.1.

Step 3:1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylicacid hydrochloride 30

To a solution of1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylicacid (Trifluoroacetic Acid) 29 (73 g, 124.7 mmol) in NMP (662.7 mL) wasadded hydrogen chloride (4M in 1,4-dioxane) (37.40 mL of 4 M, 149.6mmol). After a few seconds a yellow precipitate formed. Mixture stirredat room temperature for 20 mins, then solid collected by filtration,washed with minimal NMP then MTBE, and dried by suction to leave pureproduct 30 as a light yellow solid, (59.7 g, quantitative yield). MS(ES+) 418.1.

Step 4:2-amino-6-fluoro-N-[5-fluoro-4-[4-[4-(oxetan-3-yl)piperazine-1-carbonyl]-1-piperidyl]-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-G-32)

To a yellow suspension of1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylicacid (Hydrochloric Acid) 30 (59.7 g, 131.5 mmol) in NMP (477.6 mL) wasadded DIPEA (50.99 g, 68.72 mL, 394.5 mmol) then[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium(Boron Tetrafluoride Ion (1)) (51.44 g, 144.7 mmol). A yellow suspensionforms after a few minutes. The mixture was stirred for 30 mins at roomtemperature then 1-(oxetan-3-yl)piperazine 25 (prepared according toPreparation N-32, below) (26.18 g, 184.1 mmol) was added. The cream/tansuspension turns to an orange solution (exotherms from 23.9 to 29.4°C.). The flask was placed on ice/water bath until internal temperaturewas at 24° C., then ice bath was removed and internal temperature steadyat 24° C. thereafter.

The solution was stirred for 30 mins at room temperature then cooled onan ice/salt/water bath to 10° C. before the slow addition of water(1.015 L) in 100 mL portions. Prior to adding the next 100 mL of water,waited for exotherm to between 17° C. and 20° C. (internal) then allowto cool to between 10 and 15° C. Repeated until all water added. Onceexotherm had ceased, ice/salt/water bath removed and mixture stirred atambient temperature for 20 mins (thick yellow/cream suspension forms).Solid collected by filtration through a sinter funnel, washed well withwater then dried by suction for 10 mins. Vacuum removed and solidslurried in water on sinter funnel, then vacuum reapplied and soliddried by suction overnight then dried in vacuum oven for 24 h at 40°C.<10 mBar.

Solid (54.5 g) suspended in ethanol (545 mL, 10 vol eq.) and heatedunder reflux for 2 h then cooled to room temperature over 2 h. Solidcollected by filtration, washed with minimum ethanol and dried bysuction for 1 h to leave product as a pale yellow solid. Solid placed invacuum oven at 23.5° C. and <10 mBar overnight to leave product I-G-32as a pale yellow solid, (51 g, 64% yield). ¹H NMR (500 MHz, DMSO-d6) δ10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd, 1H), 9.26 (dd, 1H), 8.26 (d, 1H),6.79 (s, 2H), 4.55 (t, 2H), 4.47 (t, 2H), 4.34 (t, 0.7H), 3.61 (dt, 4H),3.48-3.41 (m, 2.5H), 3.22-3.17 (m, 2H), 3.05-3.03 (m, 2H), 3.99-2.93 (m,1H), 2.28 (dt, 4H), 2.17-2.10 (m, 2H), 1.74 (d, 2H), 1.07 (t, 2H). MS(ES+) 542.3.

Step 1: tert-butyl1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylate28

6-chloro-1H-benzo[d][1,2,3]triazol-1-yl2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (45 g, 129.4mmol) and tert-butyl1-(3-amino-5-fluoropyridin-4-yl)piperidine-4-carboxylate 27 (40.1 g,135.9 mmol) were slurried in pyridine (675 ml). The mixture was heatedat 95° C. under nitrogen until the reaction was complete (determined byHPLC analysis). The mixture was cooled and ethanol (450 ml) was addeddropwise. The mixture was filtered and the filter cake washed withethanol (2×70 ml). The damp cake was dried to give the product 28 as ayellow crystalline solid (47.7 g, 78%); ¹H NMR (500 MHz, DMSO-d₆) δ10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H),6.81 (s, 2H), 3.15-2.93 (m, 4H), 2.55-2.47 (masked signal, 1H),2.02-1.91 (m, 4H), 1.47 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −153.5,−136.3; MS (ES+) 474.2.

Step 2:1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylicacid 29

Tert-butyl1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylate28 (36 g, 76 mmol) was suspended in a solution of HCl in 1,4-dioxane(4M, 670 ml). Water (36 ml) was added dropwise to the rapidly stirredslurry. The mixture was stirred under nitrogen until the reaction wascomplete (determined by HPLC analysis). The mixture was diluted with1,4-dioxane (180 ml) and filtered. The filter cake was washed with TBME(2×72 ml). The damp cake was dried to give a pale brown solid(hydrochloride salt, 32.7 g, 95%); ¹H NMR (500 MHz, DMSO-d₆) δ 10.34 (s,1H), 9.53-9.49 (m, 2H), 8.82 (m, 1H), 8.50 (m, 1H), 3.13-3.22 (m, 4H),2.57-2.47 (masked signal, 1H) and 2.08-1.93 (m, 4H); 19F NMR (500 MHz,DMSO-d6) δ −152.9, −133.8; MS (ES+) 418.1.

Step 3:2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-(oxetan-3-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(compound I-G-32)

To a solution of 1-(oxetan-3-yl)piperazine (525 mg, 3.69 mmol) in THF(12 ml) was added DIPEA (1.72 ml, 9.91 mmol), followed by1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylicacid (hydrochloride salt, 1.5 g, 3.3 mmol).[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammoniumtetrafluoroborate (TCTU, 1.29 g, 3.64 mmol) was added and the mixturestirred under nitrogen until reaction completion (determined by HPLCanalysis). The mixture was cooled and water (24 ml) was added dropwise.The mixture was allowed to warm to ambient and stirred for 3 hrs, thenfiltered. The filter cake was washed with (3×3 ml). The damp cake wasdried under vacuum (with a nitrogen bleed) at 40° C. The product wasobtained as a yellow solid (1.54 g, 86%); ¹H NMR (500 MHz, DMSO-d6) δ10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd, 1H), 9.26 (dd, 1H), 8.26 (d, 1H),6.79 (s, 2H), 4.55 (t, 2H), 4.47 (t, 2H), 4.34 (t, 0.7H), 3.61 (dt, 4H),3.48-3.41 (m, 2.5H), 3.22-3.17 (m, 2H), 3.05-3.03 (m, 2H), 3.99-2.93 (m,1H), 2.28 (dt, 4H), 2.17-2.10 (m, 2H), 1.74 (d, 2H), 1.07 (t, 2H); 19FNMR (500 MHz, DMSO-d6) δ −152.8, −136.1; MS (ES+) 542.3.

Step 1: 3-(dimethoxymethyl)-4,4-dimethoxybutanenitrile 11

2-(dimethoxymethyl)-3,3-dimethoxy-propan-1-ol 10 (Journal of theAmerican Chemical Society (1973), 95(26), 8741) (92 g, 473.7 mmol) wasdissolved in dry THF (920 mL) and the mixture was cooled down with anice bath. Triethylamine (143.8 g, 198.1 mL, 1.421 mol) was added atonce, followed by dropwise addition of methane sulfonyl chloride (59.69g, 40.33 mL, 521.1 mmol), over 1 h and keeping the internal temperaturebelow 5° C. The reaction mixture was stirred for 1 h and then allowed towarm to room temperature. The mixture was diluted with ethyl acetate(920 mL) and water (920 mL). The layers were separated and the organiclayer was isolated, washed with a saturated solution of NaHCO₃, thenbrine. The organics were dried over MgSO₄, filtered and evaporated togive [2-(dimethoxymethyl)-3,3-dimethoxypropyl]methanesulfonate as anorange oil (125.31 g, 97%) which was used directly without furtherpurification.

Tetraethylammonium cyanide (142.3 g, 910.8 mmol) was added portionwiseover 10 minutes to a solution of[2-(dimethoxymethyl)-3,3-dimethoxypropyl]methanesulfonate (124 g, 455.4mmol) in MeCN (1.24 L). The reaction mixture was stirred at roomtemperature for 72 h, then portioned between ethyl acetate (1.24 L) andwater (1.24 L). The layers were separated and the organic layer wasisolated, washed with brine. The organics were dried over MgSO₄,filtered and evaporated to give3-(dimethoxymethyl)-4,4-dimethoxybutanenitrile 11 as a dark brown oil(86.1 g).

Step 2: 3-(dimethoxymethyl)-4,4-dimethoxy-2-methylbutanenitrile 12a and3-(dimethoxymethyl)-4,4-dimethoxy-2,2-dimethylbutanenitrile 13a

To a solution of 3-(dimethoxymethyl)-4,4-dimethoxy-butanenitrile 11 (250mg, 1.205 mmol) in THF (3 mL) at −75° C. was added a solution ofiodomethane (513.1 mg, 225.0 μL, 3.615 mmol) in THF (1 ml). A THFsolution of (bis(trimethylsilyl)amino)sodium (1.808 mL of 2M, 3.615mmol) was then added, keeping the temperature below −60° C. Afteraddition, the reaction mixture was stirred at −75° C. for 2 hrs and thenslowly quenched with aqueous saturated NH₄Cl solution (5 ml). Themixture diluted with water and ether and layers separated. The organiclayer was washed with brine, dried (Na₂SO₄) and concentrated in vacuo toafford a yellow oil which was purified by chromatography on silica gel,eluting with a petroleum ether:EtOAc gradient of 100:0 to 80:20.Solvents were concentrated in vacuo to afford a clear oil (194 mg). NMRproved this oil to be a mixture of 80% mono methyl compound 12a with and20% bis methyl compound 13a. This mixture was used directly insubsequent steps.

Step 3: 3-(dimethoxymethyl)-2-ethyl-4,4-dimethoxybutanenitrile 12b and3-(dimethoxymethyl)-2-diethyl-4,4-dimethoxybutanenitrile 13b

When ethyl iodide was used instead of methyl iodide in a similarprocedure to Scheme 3, step 2, above, a mixture of monosubstitutedcompound 12b and disubstituted compound 13b was isolated and useddirectly in subsequent steps.

Preparation N-1 4-(4-methylpiperazin-1-yl)pyridin-3-amine 15

Step 1: 1-methyl-4-(3-nitro-4-pyridyl)piperazine 14

4-chloro-3-nitro-pyridine (2 g, 12.61 mmol) in dioxane (15 mL) wastreated with 1-methylpiperazine (1.515 g, 1.678 mL, 15.13 mmol) andDIPEA (2.445 g, 3.295 mL, 18.92 mmol). The mixture was stirred at 80° C.for 1 hour, cooled to RT. The mixture was partioned between EtOAc and anaqueous saturated solution of NaHCO₃ (40 ml). Combined organic extractwas dried over MgSO₄ and concentrated under reduced pressure to give anorange oil which was purified by chromatography on silica eluting with5-10% MeOH/EtOAc/0.5-1% NH₄OH to give1-methyl-4-(3-nitro-4-pyridyl)piperazine 14 as a deep yellow oil whichcrystallised on standing. (2.56 g, 11.52 mmol, 91.36%). MS (ES+) 223.4.

Step 2: 4-(4-methylpiperazin-1-yl)pyridin-3-amine 15

1-methyl-4-(3-nitro-4-pyridyl)piperazine 14 (2.56 g, 11.52 mmol) inmethanol (200 mL) was treated with palladium on carbon (10% wt %Degussa) (300 mg) and hydrogenated under balloon pressure at RT for 3hours. The catalyst was filtered off and the filtrate was concentratedunder reduced pressure to give 4-(4-methylpiperazin-1-yl)pyridin-3-amine15 as a colourless solid (2.124 g, 11.05 mmol, 95.89%). MS (ES+) 193.1.

The following 3-aminopyridine intermediates were prepared usingPreparation N-1:

Miscellaneous Preparations of Aminopyridines

Preparation N-21-(3-aminopyridin-4-yl)-N,N-dimethylpiperidine-4-carboxamide

Step 1: 1-(3-amino-4-pyridyl)piperidine-4-carboxylic acid

A microwave vial was charged with methyl1-(3-amino-4-pyridyl)piperidine-4-carboxylate (prepared according tomethods similar to the one depicted in Preparation N-1) (176 mg, 0.7106mmol), MeOH (3 mL) and H₂O (0.1 mL). LiOH (51.06 mg, 2.132 mmol) wasadded and the mixture was stirred overnight at 50° C. The reaction wasquenched by addition of an aqueous solution of HCl until pH=3-4 isreached. The reaction mixture was then concentrated under reducedpressure to yield 1-(3-amino-4-pyridyl)piperidine-4-carboxylic acid thatwas used without further purification. MS (ES+) 222.1.

Step 2: 1-(3-aminopyridin-4-yl)-N,N-dimethylpiperidine-4-carboxamide

A microwave vial was charged with1-(3-amino-4-pyridyl)piperidine-4-carboxylic acid (125 mg, 0.197 mmol),TBTU (200 mg, 0.62 mmol) and N-methylmethanamine (3.5 mL, 2M in MeOH).The tube was sealed and the mixture stirred for 3 h at 120° C. The crudewas redissolved in MeOH and loaded into a MeOH pre-washed SCX column,rinsed with MeOH and the product was released with methanolic ammonia.The ammonia extracts were concentrated under reduced pressure to yield1-(3-aminopyridin-4-yl)-N,N-dimethylpiperidine-4-carboxamide. MS (ES+)249.2.

Preparation N-3 4-(4-(dimethylamino)piperidin-1-yl)pyridin-3-amine

Step 1: tert-butyl(1-(3-aminopyridin-4-yl)piperidin-4-yl)(methyl)carbamate

To a solution of tert-butylN-[1-(3-nitro-4-pyridyl)-4-piperidyl]carbamate (2100 mg, 6.514 mmol)(prepared according to methods similar to the one depicted in Step 1 ofPreparation N-1) and iodomethane (4.623 g, 2.028 mL, 32.57 mmol) in DMFat 0° C. was added portionwise sodium hydride (312.7 mg, 7.817 mmol).The reaction was stirred at 0° C. for 1 h, and at room temperature for 1h. The reaction was quenched by pouring the reaction mixture onto asaturated aqueous solution of ammonium chloride, then extracted withethyl acetate (2×50 mL). The combined organics was washed with brine(2×50 mL), dried and evaporated to leave an orange solid. To the crudesolid dissolved in MeOH (50 mL) was added Pd/C (10%) (346 mg) and themixture was stirred under a hydrogen atmosphere for 4 h. The reactionwas filtered through celite and evaporated to leave tert-butyl(1-(3-aminopyridin-4-yl)piperidin-4-yl)(methyl)carbamate as a yellowoil. (600 mg, 20%) MS (ES+−tBu) 251.1.

Step 2: 4-(4-(dimethylamino)piperidin-1-yl)pyridin-3-amine

A solution of LiAlH₄ (49.57 mg, 1.306 mmol) was added dropwise to asolution of tert-butylN-[1-(3-amino-4-pyridyl)-4-piperidyl]-N-methyl-carbamate (100 mg, 0.3264mmol) in THF at room temp. The reaction was stirred at 50° C. for 3 h,then at room temperature, the reaction mixture was quenched by thedropwise addition of wet THF. The reaction mixture was partitionedbetween 1N NaOH (50 mL) and diethyl ether (50 mL). The combined organicswas dried (MgSO₄) and evaporated to leave4-(4-(dimethylamino)piperidin-1-yl)pyridin-3-amine as a yellow oil. MS(ES+) 221.1.

Preparation N-44-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-3-amine

Step 1: 2-(methoxymethyl)-1-methyl-4-(3-nitropyridin-4-yl)piperazine

To (1-methyl-4-(3-nitropyridin-4-yl)piperazin-2-yl)methanol (preparedaccording to methods similar to the one depicted in Step 1 ofPreparation N-1) (250 mg, 0.9910 mmol) in DMF (2 mL) at 0° C. was addedNaH (59.43 mg, 1.486 mmol). The reaction mixture was stirred for 10 minbefore MeI (281.3 mg, 123.4 μL, 1.982 mmol) was added dropwise. Thereaction mixture was allowed to warm to RT and was stirred for 2 hours.The reaction mixture was loaded on a pre-washed SCX column, rinsed withMeOH and the product was released with methanolic ammonia. The ammoniaextracts were concentrated under reduced pressure. The residue waspurified by column chromatography on silica, eluting with 1-15% MeOH:DCMyielding 2-(methoxymethyl)-1-methyl-4-(3-nitropyridin-4-yl)piperazine(84 mg, 32%). MS (ES+) 237.1.

Step 2: 4-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-3-amine

To a solution of2-(methoxymethyl)-1-methyl-4-(3-nitropyridin-4-yl)piperazine (84 mg,0.31 mmol) in methanol was added Pd on C (10%, wet, Degussa) (10 mg) andthe reaction mixture was stirred overnight at room temperature under aballoon of hydrogen. The catalyst was filtered off and and the filtratewas concentrated under reduced pressure to yield4-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-3-amine as a film.(72 mg, 96%). MS (ES+) 267.1.

Preparation N-5 4-(2,4-dimethylpiperazin-1-yl)pyridin-3-amine

Step 1: 2-methyl-1-(3-nitro-4-pyridyl)piperazine

To a solution of tert-butyl3-methyl-4-(3-nitropyridin-4-yl)piperazine-1-carboxylate (preparedaccording to methods similar to the one depicted in Step 1 ofPreparation N-1) in DCM (5 mL) was added TFA (1.445 g, 976.4 μL, 12.67mmol). The reaction mixture was stirred for 48 h at RT, then the solventwas removed under reduced pressure. The crude was redissolved in MeOHand loaded into a MeOH pre-washed SCX column, rinsed with MeOH and theproduct was released with methanolic ammonia. The ammonia extracts wereconcentrated under reduced pressure to yield2-methyl-1-(3-nitro-4-pyridyl)piperazine (334 mg, 71%). MS (ES+) 223.1.

Step 2: 2,4-dimethyl-1-(3-nitropyridin-4-yl)piperazine

To 2-methyl-1-(3-nitro-4-pyridyl)piperazine in DMF (1.5 mL of 0.3 M,0.4500 mmol) at 0° C. was added NaH (18.00 mg, 0.4500 mmol). Thereaction was stirred for 10 mins then MeI (60.68 mg, 26.61 μL, 0.4275mmol) was added. The reaction mixture was stirred for 4 hours at RT andquenched by the addition of water. The crude was loaded onto a MeOHpre-washed SCX column, rinsed with MeOH and the product was releasedwith methanolic ammonia. The ammonia extracts were concentrated underreduced pressure. The residue was purified by column chromatographyeluting with 1-15% MeOH:DCM to yield2,4-dimethyl-1-(3-nitropyridin-4-yl)piperazine. MS (ES+) 237.2.

Step 3: 4-(2,4-dimethylpiperazin-1-yl)pyridin-3-amine

A solution of 2,4-dimethyl-1-(3-nitro-4-pyridyl)piperazine (89 mg,0.3767 mmol) in methanol (4 mL) and Pd on C (10%, wet, Degussa) (20 mg)was hydrogenated overnight at RT under an atmosphere of hydrogen(balloon). The catalyst was filtered off through a Celite cartridge,washed with methanol. The filtrate was concentrated under reducedpressure yielding 4-(2,4-dimethylpiperazin-1-yl)pyridin-3-amine (71 mg,91%). MS (ES+) 207.2.

Preparation N-6 4-(3,3,4-trimethylpiperazin-1-yl)pyridin-3-amine

To 4-(3,3-dimethylpiperazin-1-yl)pyridin-3-amine (prepared according tomethods similar to the one depicted in Preparation N-1) (120 mg, 0.5817mmol) in DMF (2 mL) at 0° C. was added NaH (20.94 mg, 0.5235 mmol). Thereaction mixture was stirred for 10 mins at 0° C. then MeI (276.3 uL,0.5526 mmol, 2M in TBDME) was added. The reaction mixture was allowed towarm to RT and was stirred for 2 hours at RT. The crude was loaded ontoa MeOH pre-washed SCX column, rinsed with MeOH and the product wasreleased with methanolic ammonia. The ammonia extracts were concentratedunder reduced pressure to yield4-(3,3,4-trimethylpiperazin-1-yl)pyridin-3-amine (128 mg, 73%). MS (ES+)221.1.

Preparation N-74-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-amine

Step 1: 1-(3-nitropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine

A round-bottomed flask was charged with 1-(3-nitro-4-pyridyl)piperazine(prepared according to methods similar to the one depicted in Step 1 ofPreparation N-1), dihydrofuran-3(2H)-one (98 mg, 1.13 mmol) and aceticacid (129 uL, 2.27 mmol) in MeCN (4 mL). Na(OAc)₃BH (482.4 mg, 2.27mmol) was added and the reaction mixture was stirred at RT for 1 h. Thereaction mixture was partitioned between EtOAC and an aqueous saturatedsolution of Na₂CO₃. The organic extracts were dried over MgSO₄, andconcentrated under reduced pressure to give1-(3-nitropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine as a yellowsolid. MS (ES+) 279.1.

Step 2: 4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-amine

A solution of 1-(3-nitropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine(316 mg, 1.13 mmol) in MeOH (15 mL), Pd on C (10%, wet, Degussa) (120mg) was stirred overnight at RT under an hydrogen atmosphere (balloon).The mixture was filtered through a Celite pad and concentrated underreduced pressure. The crude was redissolved in MeOH and loaded into aMeOH pre-washed SCX column, rinsed with MeOH and the product wasreleased with methanolic ammonia. The ammonia extracts were concentratedunder reduced pressure to give4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-amine as a solidwhich was used in next step without further purification. (300 mg,purity 77%, yield 82%). MS (ES+) 249.2.

The following aminopyridine were prepared according to methods similarto the one depicted in Preparation N-7:

Preparation N-8 4-(1H-pyrazol-1-yl)pyridin-3-amine

Step 1: 3-nitro-4-(1H-pyrazol-1-yl)pyridine

A suspension of pyrazole (150 mg, 2.2 mmol) and Cs₂CO₃ (526 mg, 1.6mmol) in anhydrous MeCN (3.5 mL) was stirred for 20 min under an inertatmosphere. 4-chloro-3-nitro-pyridine (233 mg, 1.47 mmol) was then addedand stirred overnight at 75° C. The insoluble was filtered off and thefiltrate was concentrated under reduced pressure yielding3-nitro-4-(1H-pyrazol-1-yl)pyridine that was used without furtherpurification. (410 mg, 98%). MS (ES+) 191.1.

Step 2: 4-(1H-pyrazol-1-yl)pyridin-3-amine

To a solution of 3-nitro-4-(1H-pyrazol-1-yl)pyridine (410 mg, 2.15 mmol)in MeOH (15 mL) was added Pd on C (10%, wet, Degussa) (129 mg) and thereaction mixture was vigorously stirred overnight at RT under anatmosphere of hydrogen (balloon). The catalyst was filtered off and thefiltrate was concentrated under reduced pressure yielding4-(1H-pyrazol-1-yl)pyridin-3-amine. (285 mg, 82%). MS (ES+) 161.1.

The following aminopyridine were prepared according to methods similarto the one depicted in Preparation N-8:

Preparation N-95-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine

Step 1: 1-(3-chloro-5-fluoropyridin-4-yl)piperazine

In a 100 mL sealed reaction vessel/bomb,3-chloro-5-fluoro-4-iodo-pyridine (5600 mg, 21.75 mmol) was taken up inNMP (12 mL). To the resulting clear brown solution was added DIPEA(3.373 g, 4.546 mL, 26.10 mmol) followed by piperazine (2.810 g, 32.62mmol). The vessel was sealed and heated thermally at 120° C. for 18 hrs.The mixture was allowed to cool to RT and was concentrated in vacuo toafford a brown gum which was purified by chromatography on silica,eluting with a gradient of DCM-DCM:MeOH:NH₃(90:10:1) 100-0 to 0:100.Fractions containing clean product were collected and concentrated invacuo to afford 1-(3-chloro-5-fluoropyridin-4-yl)piperazine as a creamsolid. (3.52 g, 75%). MS (ES+) 216.0.

Step 2: 1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine

To a suspension of 1-(3-chloro-5-fluoropyridin-4-yl)piperazine (900 mg,4.173 mmol) in THF (9.000 mL) was added 3-oxetanone (601.4 mg, 8.346mmol). To this mixture, under N₂, was added sodium triacetoxyborohydride(2.034 g, 9.598 mmol) portionwise over 5 min and the reaction mixturewas stirred at RT overnight. MeOH (2 ml) was added to the flask beforethe mixture was concentrated in vacuo. The residue was partitionedbetween water (50 ml) and EtAOc (50 ml). The aqueous phase was basifiedto pH 7-8 with NH₄OH. Combined organics washed with brine (30 ml), driedover Na₂SO₄, filtered and concentrated in vacuo to afford1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine as a creamsolid that was used in next step without further purification. MS (ES+)272.1.

Step 3: 5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine

In a pressure tube containing1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine (800 mg, 2.944mmol) was added dioxane (6 mL). To this solution was added tert-butylcarbamate (517.3 mg, 4.416 mmol), Cs₂CO₃ (1.918 g, 5.888 mmol), xantphos(85.17 mg, 0.1472 mmol) followed by Pd₂(dba)₃ (134.8 mg, 0.1472 mmol).The tube was sealed and heated thermally for 60 h at 115° C. Thereaction mixture was cooled to RT and filtered on a pad of celite. Thecake was washed with EtOAc and the combined filtrate was concentrated invacuo to a black oil. The residue was taken up in DCM (2 ml) and TFA (3ml) was added. The resulting dark brown clear solution was stirred at RTfor 2 h and then concentrated in vacuo. The residue was loaded onto aSCX-2 (10 g) cartridge. Flushed with MeOH (×3, CV) before eluting thedesired product with 2M NH₃ in MeOH (×3 CV). The basic eluent wasconcentrated in vacuo to afford a dark brown oil that was purified bychromatography on silica eluting with DCM-DCM:MeOH:NH₃(90:10:1) agradient of 100-0 to 30:70. Fractions containing product were collectedand concentrated in vacuo to afford5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine as a lightbrown solid. 295 mg: MS (ES+) 253.2.

The following aminopyridines were prepared according to methods similarto the one depicted in Preparation N-9:

Preparation N-10 5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-amine

Step 1: 1-(3-chloro-5-fluoropyridin-4-yl)-4-methylpiperazine

A solution of 3-chloro-5-fluoro-4-iodo-pyridine (2.18 g, 8.468 mmol),1-methylpiperazine (1.272 g, 1.409 mL, 12.70 mmol) and DIPEA (2.189 g,2.950 mL, 16.94 mmol) in MeCN (13.08 mL) was heated at 130° C. in themicrowave for 300 min. The reaction mixture was concentrated in vacuoand purified by column chromatography on silica eluting with 0-10%MeOH/DCM. Product fractions were combined and concentrated in vacuo toleave 1-(3-chloro-5-fluoropyridin-4-yl)-4-methylpiperazine as ayellow/brown oil. (1.16 g, 59%). MS (ES+) 230.0.

Step 2: 5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-amine

A mixture of tert-butyl carbamate (709.9 mg, 6.060 mmol), Cs₂CO₃ (3.291g, 10.10 mmol), xantphos (146.1 mg, 0.2525 mmol), Pd₂(dba)₃ (231.2 mg,0.2525 mmol) and 1-(3-chloro-5-fluoro-4-pyridyl)-4-methyl-piperazine(1.16 g, 5.050 mmol) in dioxane (11.60 mL) was heated at 110° C. for 1h. At room temperature, tert-butyl carbamate (709.9 mg, 6.060 mmol),xantphos (146.1 mg, 0.2525 mmol) and Pd₂(dba)₃ (231.2 mg, 0.2525 mmol)was added and the mixture was further heated at 120° C. in the microwavefor 1 h. The reaction mixture was then filtered through a celite pad andwashed with methanol and the filtrate concentrated in vacuo. The residuewas purified by column chromatography on silica, using the ISCO columncompanion system eluting with 0-10% MeOH/DCM. Product fractions werecombined and concentrated in vacuo to yield5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a light brownviscous oil. (642 mg, 60%). MS (ES+) 211.1.

Preparation N-11 tert-butyl4-(3-amino-5-chloropyridin-4-yl)piperazine-1-carboxylate

Step 1: tert-butyl4-(3-chloro-5-nitropyridin-4-yl)piperazine-1-carboxylate

A mixture of 4-bromo-3-chloro-5-nitro-pyridine (700 mg, 2.948 mmol),tert-butyl piperazine-1-carboxylate (823.6 mg, 4.422 mmol) and DIPEA(762.0 mg, 1.027 mL, 5.896 mmol) in NMP (2.5 mL) was stirred overnightat RT. The reaction mixture was partitioned between EtOAc and water.Combined organic extract was washed with brine, dried over MgSO₄,concentrated under reduced pressure to yield tert-butyl4-(3-chloro-5-nitropyridin-4-yl)piperazine-1-carboxylate which was usedin next step without further purification (1 g, 99%). MS (ES+) 343.1.

Step 2: tert-butyl4-(3-amino-5-chloropyridin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(3-chloro-5-nitropyridin-4-yl)piperazine-1-carboxylate (900 mg, 2.626mmol) and ZnBr₂ (118.3 mg, 28.16 μL, 0.5252 mmol) in methanol (27.00 mL)was added Pd on C (10%, wet, Degussa) (300 mg). The reaction mixture wasstirred at RT for 4 h under an atmosphere of hydrogen (balloon). Thecatalyst was filtered off and the filtrate was concentrated in vacuo toyield tert-butyl4-(3-amino-5-chloropyridin-4-yl)piperazine-1-carboxylate which was usedwithout further purification (820 mg, 99%). MS (ES+) 313.2.

The following aminopyridines were prepared according to methods similarto the one depicted in Preparation N-11:

Preparation N-12 1-methyl-4-(3-methyl-5-nitropyridin-4-yl)piperazine

Step 1: 1-methyl-4-(3-methyl-5-nitro-4-pyridyl)piperazine

To an oven dried flask under nitrogen was added1-(3-bromo-5-nitro-4-pyridyl)-4-methyl-piperazine (synthesized from3-bromo-4-chloro-5-nitropyridine according to methods similar to the onedepicted in Step 1 of Preparation N-1) (750 mg, 2.491 mmol), Pd₂dba₃(34.21 mg, 0.03736 mmol) and X-Phos (35.62 mg, 0.07473 mmol). AnhydrousTHF (37.50 mL) was added followed by 1,4-diazabicyclo[2.2.2]octanetrimethylalumane (638.6 mg, 2.491 mmol). The reaction was heated atreflux for 2 hours then cooled to ambient temperature. The reactionmixture was partitioned between water and EtOAc. The combine organicextracts were washed with brine, dried (MgSO₄) and concentrated invacuo. The residue was purified by column chromatography on silica usingthe ISCO column companion system (24 g column, Ethyl acetate/petroleumether (0-100% EtOAc)) to yield1-methyl-4-(3-methyl-5-nitro-4-pyridyl)piperazine as a yellow oil. (290mg, 49%). MS (ES+) 237.1.

Step 2: 5-methyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine

A suspension of Pd on C, (10%, wet, Degussa) (130.6 mg, 0.1227 mmol)with 1-methyl-4-(3-methyl-5-nitro-4-pyridyl)piperazine (290 mg, 1.227mmol) in methanol (5.800 mL) was stirred at rt overnight under anatmosphere of hydrogen (balloon). The reaction mixture was filteredthrough a celite pad and washed with methanol and ethyl acetate and thefiltrate concentrated in vacuo to leave5-methyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a yellow oil (243mg, 96%). MS (ES+) 207.1.

Preparation N-13(1-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone(hydrobromide) 17a

Step 1:(1-(2-bromo-5-fluoro-3-nitropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone16

A round-bottomed flask was charged with(4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (16.45g, 57.89 mmol) and DIPEA (23.20 g, 31.27 mL, 179.5 mmol) in NMP (160mL). 2, 4-Dibromo-5-fluoro-3-nitro-pyridine (17.36 g, 57.89 mmol) wasadded and the reaction mixture was stirred overnight at room temperatureunder a nitrogen atmosphere. Additional(4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (1.65 g,0.1 eq) and DIPEA (1 mL, 0.1 eq) was added and stirred at roomtemperature for a further 3 h. The mixture diluted with EtOAc, washedwith water (3×). The aqueous layer was extracted with EtOAc (3×) and thecombined organic extracts were combined, washed with brine, dried(sodium sulfate), filtered and concentrated in vacuo. The crude productwas purified by chromatography (330 g SiO₂, 0 to 5% MeOH (containing 10%ammonium hydroxide)/DCM) to afford product as a yellow solid (20.24 g,81%). MS (ES+) 432.0.

Step 2:(1-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanonehydrobromide 17a

[1-(2-Bromo-5-fluoro-3-nitro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone16 (20.24 g, 47.04 mmol) was dissolved/suspended in MeOH (389 mL)/EtOAc(78 mL) and Pd(OH)₂ (1.651 g, 2.352 mmol) was added. The resultingmixture was degassed by vacuum/nitrogen cycles (×5) and the atmospherewas exchanged by vacuum/hydrogen cycles (×5). The reaction mixture wasstirred vigorously under a hydrogen atmosphere (balloon) for 6 hrs.Additional Pd(OH)₂ (4.95 g) was added and the reaction mixture wasstirred overnight under hydrogen. The mixture was filtered throughcelite, washing through with methanol. The filtrate was concentrated invacuo to leave an orange gum. Approx. 150 mL of ethanol was added andthe mixture rotated on buchii for 10 mins, a yellow precipitate hadformed during this time. The suspension was sonicated for 5 mins and thesolid was then collected by filtration, washed with minimal ethanol anddried by suction for 1 h to afford product as a pale yellow solid. Asecond crop of product was obtained by concentrating the filtrate invacuo. The residue was then slurried in minimal ethanol and sonicatedfor 5 mins then solid collected by filtration, dried by suction to leavesecond crop of product as a yellow solid. Both crops of product werecombined to afford product as a yellow solid (15.8 g, 79%). MS (ES+)322.2.

Preparation N-14(1-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone(hydrochloride) 17b

Step 1: 3-bromo-4-chloro-5-fluoropyridine hydrochloride 18

To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF(75 mL) cooled to −78° C., was added butyllithium (25 mL of 2.5 M inhexanes, 62.5 mmol). The reaction mixture was allowed to warm to −20° C.then cooled back down to −78° C. A solution of 3-bromo-5-fluoro-pyridine(10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperaturebelow −70° C. (approx 30 mins). The reaction mixture was stirred at −78°C. for 30 min and a solution of 1,1,1,2,2,2-hexachloroethane (14.8 g,62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperaturebelow −70° C. (over approx 30 mins). The mixture was stirred at −78° C.for 20 minutes, allowed to warm to room temperature, cooled back to 0°C. and quenched with water (100 mL). EtOAc (400 mL) was then added, andorganic layer separated, washed with water (2×), brine (1×), dried(MgSO₄), filtered and concentrated in vacuo to leave a brown solid. Thesolid was triturated in pentane (100 mL) for 10 minutes, then filtered.The filtrate was concentrated in vacuo to afford product as a brown oilthat turned to a crystalline solid on standing, 11.85 g, 89%). ¹H NMR(DMSO-d6) δ 8.78 (s, 1H), 8.76 (s, 1H).

To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol)in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mLof 2 M, 35.4 mmol). An off-white precipitate formed instantly. Themixture was stirred for 5 minutes then the solid was collected byfiltration, washed with pentane and dried by suction to afford thedesired product as an off-white solid (4.79 g, 60%). ¹H NMR (DMSO-d6) δ8.77 (s, 1H), 8.75 (s, 1H).

Step 2:(1-(3-bromo-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone

A mixture of (4-methylpiperazin-1-yl)-(4-piperidyl)methanonedihydrochloride (50.65 g, 178.2 mmol),3-bromo-4-chloro-5-fluoro-pyridine hydrochloride 18 (40 g, 162 mmol) anddipotassium carbonate (94.04 g, 680.4 mmol) in NMP (400 mL) was heatedat 150° C. overnight. The mixture was cooled to room temperature thenfiltered to remove inorganic salts and the filtrate was concentrated invacuo. The residue was dissolved in EtOAc (800 mL), washed with brine(100 mL×4), dried (MgSO₄), filtered and concentrated in vacuo to afforda brown viscous oil. This residue was purified by silica gel column(approx 800 g of silica), product loaded onto silica in DCM, theneluting with 3% methanol (containing 10% ammonium hydroxide)/DCM toafford the desired product as a brown oil which crystallised on standing(27.44 g, 44%). MS (ES+) 387.1.

Step 3:(1-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanonehydrochloride 17b

Pd₂(dba₃) (3.818 g, 4.169 mmol) and Xantphos (4.824 g, 8.337 mmol) wereadded to a degassed (3×vacuum/N₂ cycles) mixture of diphenylmethanimine(16.62 g, 15.39 mL, 91.71 mmol),[1-(3-bromo-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone19 (32.12 g, 83.37 mmol), tert-butyl carbamate (3.649 g, 31.15 mmol),and Cs₂CO₃ (81.49 g, 250.1 mmol) in dioxane (550 mL) in a round bottomflask under N₂. The reaction mixture was flushed with nitrogen via2×vacuum/N₂ cycles then stirred at 100° C. overnight under N₂. Themixture cooled to room temperature then partitioned between EtOAc (1 L)and water (100 mL). The organic layer was separated, washed with water(2×100 mL), brine (1×100 mL), dried (MgSO₄), filtered and concentratedin vacuo to afford a dark orange viscous oil (56.15 g). This cruderesidue was then dissolved in THF (482 mL) and hydrogen chloride (300 mLof 2 M, 600 mmol) and the mixture was heated at 60° C. for 30 minutes.THF was removed in vacuo and the remaining aqueous solution was washedwith EtOAc (2×) then basified to pH=8 with 2M NaOH solution (approx. 310mL), and extracted with EtOAc (3×). The combined organic extracts werewashed with brine (1×), dried (MgSO₄), filtered and concentrated invacuo to afford an orange solid (25.44 g). The orange solid wasdissolved in dioxane (300 mL) then 4M HCl in dioxane (19.8 mL, 79.16mmol) was added slowly over 10 mins. The mixture was stirred for 20minutes and the precipitate that formed was collected by filtration,washed with dioxane (approx 100 mL), diethyl ether (100 mL), dried bysuction to afford desired product as a white solid (25.13 g, 84%). MS(ES+) 322.2.

Step 3a:(1-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone

In an alternative method to Step 3, above,Tris(dibenzylideneacetone)dipalladium (1.189 g, 1.298 mmol) and xantphos(1.502 g, 2.596 mmol) were added to a degassed (3×vacuum/N₂ cycles)mixture of[1-(3-bromo-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone19 (10 g, 25.96 mmol) and Cs₂CO₃ (16.92 g, 51.92 mmol) in dioxane (150mL) under N₂. The mixture was stirred at 100° C. overnight. The reactionwas cooled to ambient temperature and the precipitate was filtered offand washed with EtOAc (50 mL). The filtrate was partitioned betweenEtOAc and water. The combined organic layers were washed with water,brine, dried (MgSO₄) and concentrated in vacuo to leave tert-butylN-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]carbamateas a red solid that was used in next step without further purification.MS (ES+) 422.2.

To a suspension of tert-butylN-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]carbamate(3.34 g, 7.924 mmol) in dioxane (25 mL) was added HCl (4M in dioxane) (8mL of 4 M) and the mixture was heated at 40° C. overnight. The mixturewas cooled to RT and the solid was collected by filtration, washed withdioxane (15 mL) then with EtOAc (2×20 ml) and dried in vacuo to leave awhite solid which was partitioned between EtOAc (70 ml) and 1M sodiumcarbonate (50 ml). Combined organic extract was dried and concentratedin vacuo to yield 2.26 g of an off-white solid that was slurried in MeCN(5 mL). The solid was collected by filtration, washed with minimal MeCN(3 to 5 mL), and dried by suction to leave(1-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanoneas a white solid. MS (ES+) 322.1.

The following aminopyridine intermediates were prepared using aprocedure similar to either Preparation N-13 or Preparation N-14:

Preparation N-15 tert-butyl1-(3-amino-5-fluoro-4-pyridyl)piperidine-4-carboxylate

Step 1: tert-butyl1-(3-bromo-5-fluoro-4-pyridyl)piperidine-4-carboxylate 26

A 3 L flange flask equipped with a thermometer, condensor, nitrogen lineand overhead stirrer was heated at 40° C. (external) then charged withcyclohexanol (750 mL), disodium carbonate (129.8 g, 1.225 mol),3-bromo-4-chloro-5-fluoro-pyridine (Hydrochloric Acid 18) (137.5 g,556.8 mmol) and tert-butyl piperidine-4-carboxylate (123.8 g, 668.2mmol) rinsed in with cyclohexanol (350 mL). Mixture was heated to 120°C. internal temperature overnight (18 h). Reaction mixture was removedfrom hotplate and allowed to cool to room temperature. Water (687.5 mL)and EtOAc (687.5 mL) were added, stirred for 10 mins then transferred toseparating funnel. Additional EtOAc (1.238 L) was added, mixed andaqueous phase was removed. Organic phase was further washed with water(687 mL), aqueous phase removed, organic layer collected. Aqueous phaseswere combined and back extracted with EtOAc (687.5 mL), aqueous layerremoved and organic phase combined with other organics. Organicsconcentrated in vacuo (water bath temp=60° C., vacuum down to 2 mBar)leaving a viscous brown oil.

Oil was dissolved in 25% EtOAc/petrol then passed through a short silicapad, eluting with 25% EtOAc/petrol until no more product came off.Filtrate was concentrated in vacuo to leave a brown oil, 127.1 g.Product re-purified by ISCO companion (1.5 Kg Silica, loaded in DCM,eluting 0 to 20% EtOAc/petrol), product fractions combined andconcentrated in vacuo to leave desired product 26 as a pale yellow tocream solid, (98 g, 49% yield). ¹H NMR (500 MHz, DMSO-d6) δ 8.47 (s,1H), 8.41 (d, 1H), 3.39-3.36 (m, 2H), 3.12 (tt, 2H), 2.49-2.43 (m, 1H),1.91-1.87 (m, 2H), 1.71-1.64 (m, 2H) and 1.43 (s, 9H). MS (ES+) 361.0.

Step 2: tert-butyl1-(3-amino-5-fluoro-4-pyridyl)piperidine-4-carboxylate 27

To a solution of tert-butyl1-(3-bromo-5-fluoro-4-pyridyl)piperidine-4-carboxylate 26 (98 g, 272.8mmol), diphenylmethanimine (59.34 g, 54.94 mL, 327.4 mmol) and Cs2CO3(177.8 g, 545.6 mmol) in Dioxane (1.274 L) was added xantphos (15.78 g,27.28 mmol) and Pd2(dba)₃ (12.49 g, 13.64 mmol). The mixture was stirredunder nitrogen at 95° C. overnight. The mixture was cooled to roomtemperature then partitioned between EtOAc (1000 mL, 10 vol eq.) andwater (490 mL, 5 vol eq.), mixed and organic layer separated. Organicswashed further with water (1×250 mL), brine (250 mL), dried (MgSO₄),filtered and concentrated in vacuo to leave crude product as a dark redviscous oil, 185.3 g.

The obtained product oil (185.3 g) was dissolved in THF (882.0 mL) andHCl (545.5 mL of 2 M, 1.091 mol) was added. The resulting mixture wasstirred at room temperature for 20 mins. THF was removed in vacuo thenadditional (HCl (2M) (588.0 mL) was added. The aqueous was washed twicewith EtOAc (294.0 mL). A large amount of a yellow precipitate formedduring extraction in both organic and aqueous phase, the solid from boththe organic and aqueous phase was collected by filtration and dried bysuction. The mixed organic and aqueous filtrate was added to separatingfunnel, extracted with 2M HCl (2×200 mL). All aqueous phases plus solidcollected on sinter (product) were combined to give a suspension. The pHwas adjusted to 6 using 2M NaOH and extracted with DCM (3×600 mL). Theorganics were combined, dried (MgSO₄), filtered and concentrated invacuo to leave a pale orange waxy solid, 112.2 g. This solid wasslurried in MeCN (200 mL), stirred for 10 mins then solid collected byfiltration, washed with minimal MeCN and dried by suction to leaveproduct 27 as a white solid (66.8 g, 83% yield). ¹H NMR (500 MHz,DMSO-d6) δ 7.82 (d, 1H), 7.63 (d, 1H), 5.22 (s, 2H), 3.11-3.00 (m, 2H),2.91 (tt, 2H), 2.36 (tt, 1H), 1.88-1.83 (m, 2H), 1.79-1.71 (m, 2H), 1.43(s, 9H). MS (ES+) 297.1.

Step 1: 3-bromo-4-chloro-5-fluoropyridine hydrochloride 18

A solution of diisopropylamine (101.2 g, 140.2 mL, 1.000 mol) intetrahydrofuran (1.148 L) was cooled to between −25° C. and −20° C.Butyllithium (2.5M in hexanes) (400 mL of 2.5 M, 1.000 mol) was added atsuch a rate as to maintain the reaction temperature below −20° C.(addition 20 minutes). The mixture was then allowed to warm to 4° C.over 1 hour, then re-cooled to −78° C. 3-bromo-5-fluoro-pyridine (153.0g, 869.6 mmol) in tetrahydrofuran (382.5 mL) was added over 40 minutes.The mixture was stirred for 90 minutes, then a solution of1,1,1,2,2,2-hexachloroethane (205.9 g, 869.6 mmol) in tetrahydrofuran(350.0 mL) was added dropwise over 40 minutes. Once the addition wascomplete the mixture was allowed to warm to ambient overnight. Themixture was cooled to 0° C. then transferred into cold water (2 L),stirred for 20 mins then MTBE (2.5 L) added and stirred vigorously for30 mins then transferred to separating funnel and organic layerseparated. Aqueous was transferred back to reaction vessel and furtherextracted with MTBE (2.5 L), stirred for 10 mins vigorously thentransferred to separating funnel and organic layer separated. Organicswere combined, dried (MgSO₄), filtered and concentrated to a brown oil.The oil was dissolved in pentane (500 ml) and ether (300 ml). HCl (2M inether) (434.8 mL of 2 M, 869.6 mmol) was added slowly with stirring. Oncomplete addition the mixture was stirred for 20 mins then solidcollected by filtration, washed with ether and dried under vacuum for 1h to leave product 18 as a beige solid (148.9 g, 69%); ¹H NMR (500 MHz,DMSO-d6) δ 8.77 (2H, s); 19F NMR (500 MHz, DMSO-d6) δ −124.8; MS 210.8.

Step 2: tert-butyl1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26

3-bromo-4-chloro-5-fluoro-pyridine hydrochloride 18 (62 g, 251.1 mmol)was suspended in DCM (600 mL) and stirred. The mixture was cooled in anice bath and sodium hydroxide (276.2 mL of 1 M, 276.2 mmol) was addedslowly. The resulting mixture was stirred for 1 hour. The mixture wasphase-separated. More DCM/water was added to aid phase separation. Sometarry particulates remained in the aqueous phase. The organic phase waswashed with brine, dried (MgSO₄), filtered and concentrated. The residuewas triturated with heptane. The heptane solution was filtered through aflorsil pad, eluting with heptane. The filtrate was concentrated to anoil which solidified. This gave 41 g of free base.

A thoroughly stirred mixture of 3-bromo-4-chloro-5-fluoropyridine freebase (55 g, 0.26 mol), potassium fluoride (31 g, 0.53 mol) and Me₄NCl(5.8 g, 53 mmol) in DMSO (400 mL) was heated to 130° C. for 2 hours. Thereaction mixture was cooled to room temperature and tert-butylpiperidine-4-carboxylate hydrochloride 22 (66 g, 0.30 mol) and DIPEA (65g, 0.50 mol) were added. The reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated in vacuo. The residuewas portioned between DCM/water. The organic layer was washed with water(3×), dried over Na₂SO₄, and filtered over silica gel using DCM aseluent. The filtrated was evaporated to give tert-butyl1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26 (61 g, 65%)as a light yellow solid; 1H NMR (500 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.41(d, 1H), 3.39-3.36 (m, 2H), 3.12 (tt, 2H), 2.49-2.43 (m, 1H), 1.91-1.87(m, 2H), 1.71-1.64 (m, 2H) and 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6)δ −135.2; MS (ES+) 361.0.

Step 3: tert-butyl1-(3-amino-5-fluoropyridin-4-yl)piperidine-4-carboxylate 27

Tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26(800 g, 2.23 mol) was dissolved in 1,4-dioxane (7.5 L).Diphenylmethanimine (484 g, 2.67 mol) was added in one portion followedby cesium carbonate (1.45 Kg, 4.45 mol), xantphos (129 g, 223 mmol) andPd₂(dba)₃ (102 g, 111 mmol). Additional 1,4-dioxane (2.9 L) was addedand the mixture heated to 95° C. under nitrogen until the reaction wascomplete (determined by HPLC analysis). The mixture was cooled to 20° C.and ethyl acetate (8 L) and water (4 L) were added. The organic phasewas isolated and washed with water (4 L) and brine (3.5 L) and driedover magnesium sulphate and filtered. The filtrate was concentrated to abrown oil (1.3 Kg). The oil was dissolved in 2-methyltetrahydrofuran(7.2 L) and 2M HCl was added at 20° C. and the mixture stirred for 30minutes. The aqueous layer was isolated and the organic layer extractedwith 2M HCl (1.2 L). The combined aqueous was neutralised with 2M NaOH(5.4 L, pH 8-9). The product was extracted into 2-methyltetrahydrofuran(14 L then 2×5 L). The combined extracts were washed with water (1.6 L)and the organic solution concentrated. The residue was slurried inacetonitrile (2 L), filtered and dried. This gave the product 27 as awhite solid (568.7 g, 86.5%); 1H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, 1H),7.63 (d, 1H), 5.22 (s, 2H), 3.11-3.00 (m, 2H), 2.91 (tt, 2H), 2.36 (tt,1H), 1.88-1.83 (m, 2H), 1.79-1.71 (m, 2H), 1.43 (s, 9H); 19F NMR (500MHz, DMSO-d6) δ −140.0; MS (ES+) 297.1.

Preparation N-16 5-cyclopropyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine

Step 1: 1-(3-cyclopropyl-5-nitropyridin-4-yl)-4-methylpiperazine

A mixture of 1-(3-bromo-5-nitro-4-pyridyl)-4-methyl-piperazine(synthesized from 1-methylpiperazine and3-bromo-4-chloro-5-nitropyridine using procedure Step 1 of PreparationN-1) (467.4 mg, 1.552 mmol), ferrous;dichloro-bis[cyclopenta-1,4-dien-1-yl(diphenyl)phosphaniumyl]palladium(2-);dichloromethane (63.37 mg, 0.07760 mmol), potassium carbonate (429.0 mg,3.104 mmol) and cyclopropylboronic acid (200.0 mg, 2.328 mmol) indioxane (5 mL) was degassed and flushed with nitrogen (×2). The reactionwas heated at 100° C. in a sealed tube for 18 h. At room temperature thereaction mixture was filtered through Celite and evaporated to dryness,yielding 1-(3-cyclopropyl-5-nitropyridin-4-yl)-4-methylpiperazine as adark orange solid that was used directly in the next reaction withoutfurther purification (288 mg, 66%). MS (ES+) 263.2

Step 2: 5-cyclopropyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine

To a solution of 1-(3-cyclopropyl-5-nitro-4-pyridyl)-4-methyl-piperazine(220.4 mg, 0.8403 mmol) in methanol (25 mL) was added Pd on carbon (10%,Degussa, 6.387 mg, 0.006002 mmol). The reaction mixture was stirred atroom temperature under a balloon of hydrogen, for 7 h. The reaction wasfiltered through a plug of Celite, washed with MeOH and the filtrate wasconcentrated in vacuo yielding5-cyclopropyl-4-(4-methylpiperazin-1-yl)pyridin-3-amine as an orangeresidue. (194 mg, 99%).

Preparation N-17 6-chloro-4-(4-methylpiperazin-1-yl)pyridin-3-amine

Step 1: 1-(2-chloro-5-nitropyridin-4-yl)-4-methylpiperazine

1-methylpiperazine (298.5 mg, 330.6 μL, 2.980 mmol) in THF (5 mL) wasadded to a stirred solution of 2,4-dichloro-5-nitro-pyridine (500 mg,2.591 mmol) and DIPEA (401.8 mg, 541.5 μL, 3.109 mmol) in THF (10 mL) at0° C. under an atmosphere of nitrogen. The reaction was allowed to stirat ambient temperature for 1 hour then the solvent removed in vacuo. Theresidue was purified by column chromatography (ISCO Companion, 40 gcolumn, eluting with 0 to 10% MeOH/DCM solutions) to give1-(2-chloro-5-nitropyridin-4-yl)-4-methylpiperazine as a yellow solid(638 mg, 96% Yield). MS (ES+) 257.1.

Step 2: 6-chloro-4-(4-methylpiperazin-1-yl)pyridin-3-amine

1-(2-chloro-5-nitro-4-pyridyl)-4-methyl-piperazine (580 mg, 2.260 mmol)was dissolved in AcOH (20 mL)/Water (2 mL) and Fe (2.524 g, 45.20 mmol)was added. The resulting mixture was stirred at 50° C. for 30 minutes.The reaction was cooled to ambient temperature then loaded onto 50 gSCX-2 cartridge (pre-washed with MeOH). The cartridge was washed withDCM/MeOH mixtures, before the product was eluted with 2M NH₃ in MeOH/DCMmixtures. The solvent was removed in vacuo to give6-chloro-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a purple solid(510 mg, 99% Yield). MS (ES+) 227.1.

Preparation N-18 4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine

Step 1: 4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine

1-methylpiperazine (265.5 mg, 294.0 μL, 2.651 mmol) in THF (5 mL) wasadded to a stirred suspension of 4-chloro-5-nitro-pyridin-2-amine (400mg, 2.305 mmol) and DIPEA (357.5 mg, 481.8 μL, 2.766 mmol) in THF (10mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowedto stir at ambient temperature for 90 hours before the solvent removedin vacuo. The residue was tritruated from DCM/MeOH and the resultantprecipitate was washed with DCM/MeOH solutions. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography (ISCO Companion, 40 g column, eluting with 0 to 10% 2MNH₃ in MeOH/DCM) to give4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine as a yellow solid(355 mg, 65% Yield). MS (ES+) 238.1.

Step 2: 4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine

Pd on C, (10%, wet, Degussa) (140 mg, 0.1316 mmol) was added to astirred solution of 4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine(355 mg, 1.496 mmol) in a mixture of EtOAc (5 mL) and EtOH (50 mL). Thereaction was placed under an atmosphere of hydrogen and stirred atambient temperature for 16 hours. The catalyst was removed by filtrationthrough a pad of celite and the filtrate concentrated in vacuo to give4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine as a brown solid (291 mg,94% Yield). MS (ES+) 208.1.

Preparation N-195-(difluoromethyl)-4-(4-methylpiperazin-1-yl)pyridin-3-amine

Step 1: 5-bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine

1-methylpiperazine (2.109 g, 21.06 mmol) in DCM (62.50 mL) was added toa stirred solution of 3-bromo-4-chloro-5-nitro-pyridine (5000 mg, 21.06mmol) and DIPEA (3.266 g, 4.402 mL, 25.27 mmol) in DCM (62.50 mL) at RT.The reaction was allowed to stir at ambient temperature for 2 h, thenwas concentrated in vacuo. The residue was partitioned between asaturated aqueous solution of NaHCO₃ and DCM. Combined organic extractwas dried and concentrated in vacuo. The orange solid was suspended inAcetic acid (60.00 mL) before iron (7.059 g, 126.4 mmol) was added. Themixture was warmed at 50° C. and stirred for 15 min. The mixture wasallowed to cool to RT and DCM:EtOAc (4:1) (400 mL) was added to thereaction. The resulting brown suspension was filtered using a prewettedCelite cartridge (25 g), washing with more DCM:MeOH (4:1) (200 mL).Combined filtrate was concentrated in vacuo to afford a red/brown gumwhich was purified by chromatography on silica (Rf companion, 80 gcartridge), eluting with DCM-DCM:MeOH:NE3 (90:10:1) a gradient of 100-0to 20:80. Fractions containing clean product were collected andconcentrated in vacuo to afford5-bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a viscous, clearlight yellow oil that solidifies on standing. MS (ES+) 273.1.

Step 2:1-(3-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl)-4-methylpiperazine

5-bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine (3000 mg, 11.06 mmol),hexane-2,5-dione (6.312 g, 6.487 mL, 55.30 mmol) in acetic acid (20 mL)was heated at 70° C. overnight. The reaction mixture was concentrated invacuo and the residue was partitioned between EtOAc and an aqueoussaturated solution of NaHCO₃. Combined organic extract was washed withbrine, dried (MgSO₄) and concentrated in vacuo yielding an oil that waspurified by filtration on silica to yield1-(3-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl)-4-methylpiperazineas an off-white solid. MS (ES+) 351.1.

Step 3:5-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(4-methylpiperazin-1-yl)nicotinaldehyde

A solution of1-[3-bromo-5-(2,5-dimethylpyrrol-1-yl)-4-pyridyl]-4-methyl-piperazine(1250 mg, 3.579 mmol) in THF (35.79 mL) was cooled to −78° C. and t-BuLi(2.105 mL of 1.7 M, 3.579 mmol) was added dropwise. The mixture wasstirred for 30 mins at −78° C. before DMF (261.6 mg, 277.1 μL, 3.579mmol) was added dropwise. The mixture was stirred for 2 h at −78° C. Thereaction was quenched with MeOH (5 mL) and allowed to warm to roomtemperature. The reaction was washed with an aqueous saturated solutionof ammonium chloride (50 mL) and extracted with EtOAc (100 mL and 50mL). The combined organics were dried (MgSO₄) and evaporated to leave anorange oil. Purification by column chromatography (EtOAc to EtOAc:MeOH20%) yielded5-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(4-methylpiperazin-1-yl)nicotinaldehydeas a pale yellow crystalline solid. MS (ES+) 299.2.

Step 4:1-(3-(difluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl)-4-methylpiperazine

To a solution of5-(2,5-dimethylpyrrol-1-yl)-4-(4-methylpiperazin-1-yl)pyridine-3-carbaldehyde(100 mg, 0.3351 mmol) in methylene chloride (335.1 μL) at RT was added2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-{4}-sulfanyl)ethanamine (370.8mg, 1.676 mmol) and the mixture was heated at reflux for 18 h. At roomtemperature, the reaction was quenched with water (2 mL) and extractedwith methylene chloride (2×5 mL) to yield1-(3-(difluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl)-4-methylpiperazineas a yellow oil. MS (ES+) 321.2.

Step 5: 5-(difluoromethyl)-4-(4-methylpiperazin-1-yl)pyridin-3-amine

A solution of1-[3-(difluoromethyl)-5-(2,5-dimethylpyrrol-1-yl)-4-pyridyl]-4-methyl-piperazine(80 mg, 0.2497 mmol) and NH₂OH (165.0 mg, 4.994 mmol) in a mixture oftriethylamine (101.1 mg, 139.3 μL, 0.9988 mmol), ethanol (1 mL) and H₂O(0.25 mL) was heated at reflux for 20 h. After cooling to RT thereaction was quenched by loading directly onto an SCX-2 cartridge andeluted with MeOH followed by NH₃/MeOH. The basic fraction wasconcentrated in vacuo yielding5-(difluoromethyl)-4-(4-methylpiperazin-1-yl)pyridin-3-amine that wasused in next step without further purification. MS (ES+) 243.1.

Preparation N-20(S)-5-fluoro-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-amine

Step 1:(S)-1-(3-chloro-5-fluoropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine

MsCl (393.3 mg, 265.7 μL, 3.433 mmol) was added to a solution of(3R)-tetrahydrofuran-3-ol (275 mg, 3.121 mmol) and Et₃N (379.0 mg, 522.0μL, 3.745 mmol) in DCM (5 mL) at 0° C. and the resulting solutionstirred at RT overnight. The reaction mixture was diluted with water (5mL) and DCM (5 mL) and the layers separated. The aqueous layer wasextracted further with DCM (2×5 mL) and the combined organic extractswashed with saturated aqueous sodium hydrogen carbonate solution (1×5mL), dried over MgSO₄ and concentrated in vacuo. The residue was takenup in n-BuOH (5 mL) and 1-(3-chloro-5-fluoro-4-pyridyl)piperazine (1.010g, 4.682 mmol) was added and the reaction mixture heated at 118° C.overnight. The reaction mixture was cooled to RT and concentrated invacuo. The residue was purified by column chromatography on silica (24 gcolumn, 0-100% EtOAc/petroleum ether). Product fractions were combinedand concentrated in vacuo to leave(S)-1-(3-chloro-5-fluoropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazineas an off white solid. MS (ES+) 288.1.

Step 2:(S)-5-fluoro-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-amine

BrettPhos pre-catalyst (4.183 mg, 0.005250 mmol) and BrettPhos (2.818mg, 0.005250 mmol) were added to a solution of tert-butyl carbamate(153.7 mg, 1.312 mmol), sodium tert-butoxide (128.7 mg, 1.339 mmol) and1-(3-chloro-5-fluoro-4-pyridyl)-4-[(3S)-tetrahydrofuran-3-yl]piperazine(75 mg, 0.2625 mmol) in toluene (1.500 mL) and the resulting mixturesealed (reaction in a microwave tube) and placed into a preheated drysynblock at 100° C. and heated for 6 h. Additional BrettPhos pre-catalyst(4.183 mg, 0.005250 mmol) and BrettPhos (2.818 mg, 0.005250 mmol) wereadded and the reaction mixture was resealed and heated at 100° C.overnight. The reaction mixture was cooled to RT and quenched byaddition of saturated aqueous NH₄Cl and then filtered through a celitepad washing with ethyl acetate. The filtrate was extracted with ethylacetate (2×5 mL) and the combined organic extracts were dried over MgSO₄and concentrated in vacuo to leave a pale yellow oil (102 mg). Theresidue was taken up in DCM (2 mL) and TFA (299.3 mg, 202.2 μL, 2.625mmol) was added and the resulting solution stirred at rt for 2 h. Themixture was concentrated in vacuo and passed through an SCX cartridgeeluting the product with 2M ammonia in methanol. The filtrate wasconcentrated in vacuo and purified by column chromatography on silicaeluting with 0-20% MeOH/DCM, 4 g column. Product fractions were combinedand concentrated in vacuo to leave the product as a colourless oil. MS(ES+) 267.2.

Preparation N-21N2-methyl-4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine

Step 1: 1-(2-chloro-5-nitropyridin-4-yl)-4-methylpiperazine

1-methylpiperazine (119.3 mg, 132.6 μL, 1.191 mmol) in THF (1.5 mL) wasadded to a stirred solution of 2,4-dichloro-5-nitro-pyridine (200 mg,1.036 mmol) and DIPEA (160.6 mg, 216.4 μL, 1.243 mmol) in THF (3.000 mL)at 0° C. under an atmosphere of nitrogen. The reaction was allowed tostir at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and NaHCO₃ (sat. aq. soln). Thecombined organics was washed with brine, dried over MgSO₄ andconcentrated under reduced pressure to yield1-(2-chloro-5-nitro-4-pyridyl)-4-methyl-piperazine. (100%) MS (ES+)257.1.

Step 2: N-methyl-4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine

1-(2-chloro-5-nitro-4-pyridyl)-4-methyl-piperazine (265.9 mg, 1.036mmol) and methylamine 2M in THF (2.590 mL of 2 M, 5.180 mmol) wereheated overnight in a sealed tube at 60° C. The mixture was purified bychromatography on silica (Companion 12 g) eluting with 0.5-15% MeOH:DCM,yielding N-methyl-4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine(243 mg, 93%). MS (ES+) 252.1.

Step: 3: N2-methyl-4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine

N-methyl-4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine (243 mg,0.9670 mmol) was dissolved in methanol (10 mL) and Pd on C, wet, Degussa(50 mg, 0.4698 mmol) was added. The reaction was evacuated and filledwith hydrogen three times and left to stir at RT overnight. The catalystwas filtered off and the solvent was removed under reduced pressure toyield N2-methyl-4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine (173 mg,81%). MS (ES+) 222.1.

Preparation N-225-fluoro-4-(4-((4-methylpiperazin-1-yl)sulfonyl)piperidin-1-yl)pyridin-3-amine

Step 1: 1-(3-chloro-5-fluoropyridin-4-yl)piperidin-4-ol

To a solution of 3-chloro-5-fluoro-4-iodo-pyridine (1 g, 3.885 mmol) inNMP (1 mL) was added DIPEA (753.1 mg, 1.015 mL, 5.828 mmol) andpiperidin-4-ol (589.4 mg, 5.828 mmol) and the mixture heated to 120° C.for 4 hours. The mixture was diluted with ethyl acetate (30 ml), washedtwice with water (20 ml) and with brine. The organic layer was driedwith MgSO₄ and concentrated in vacuo to a yellow solid that was purifiedby column chromatography using DCM and then 2% MeOH/DCM as eluent,yielding 1-(3-chloro-5-fluoro-4-pyridyl)piperidin-4-ol. MS (ES+) 231.0.

Step 2: S-(1-(3-chloro-5-fluoropyridin-4-yl)piperidin-4-yl)ethanethioate

isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (723.1 mg, 3.576 mmol)was added dropwise to a solution of1-(3-chloro-5-fluoro-4-pyridyl)piperidin-4-ol (750 mg, 3.251 mmol) andTriphenylphosphine (937.9 mg, 828.5 μL, 3.576 mmol) in THF at −20° C.After stirring for 15 mins, ethanethioic S-acid (272.2 mg, 255.6 μL,3.576 mmol) was added, the mixture was allowed to warm to roomtemperature and was stirred for a further 30 minutes. The mixture wasthen diluted with ethylacetate (30 ml), washed twice with water (20 ml)and with brine. The organic layer was dried with MgSO₄ and concentratedin vacuo to a yellow solid that was purified by column chromatographyeluting with 5/95 ether/pet ether to elute side products and then 10/90ether/pet ether. The relevant fractions were combined and concentratedin vacuo to afford S-(1-(3-chloro-5-fluoropyridin-4-yl)piperidin-4-yl)ethanethioate as a green solid. MS (ES+) 289.0.

Step 3: 1-(3-chloro-5-fluoropyridin-4-yl)piperidine-4-sulfonyl chloride

To a mixture of HCl (1.038 mL of 2 M, 2.077 mmol) and MeCN (8 mL) wasadded NCS (693.4 mg, 5.193 mmol) and the mixture cooled to 10° C. andstirred until most of the NCS (693.4 mg, 5.193 mmol) was dissolved. Asolution of S-[1-(3-chloro-5-fluoro-4-pyridyl)-4-piperidyl]ethanethioate (500 mg, 1.731 mmol) in MeCN (8 mL) was added dropwise.The solution was stirred for 30 minutes at 10° C., diluted with etherand washed with dilute brine. The organic layer was dried with MgSO₄ andconcentrated in vacuo to yield1-(3-chloro-5-fluoropyridin-4-yl)piperidine-4-sulfonyl chloride as ayellow solid. MS (ES+) 313.0.

Step 4:1-((1-(3-chloro-5-fluoropyridin-4-yl)piperidin-4-yl)sulfonyl)-4-methylpiperazine

To a solution of 1-(3-chloro-5-fluoro-4-pyridyl)piperidine-4-sulfonylchloride (400 mg, 1.277 mmol) in DCM (5 mL) was added TEA (129.2 mg,178.0 μL, 1.277 mmol) followed by 1-methylpiperazine (255.8 mg, 2.554mmol). The mixture was stirred at room temperature for 1 h. The mixturewas diluted with ethylacetate (30 ml), washed twice with water (20 ml)and with brine. The organic layer was dried with MgSO₄ and concentratedin vacuo to a yellow solid. The product was purified by columnchromatography eluting with 5/95 methanol/DCM. The relevant fractionswere combined and concentrated in vacuo to afford the1-((1-(3-chloro-5-fluoropyridin-4-yl)piperidin-4-yl)sulfonyl)-4-methylpiperazineasa green solid. MS (ES+) 377.1.

Step 5:5-fluoro-4-(4-((4-methylpiperazin-1-yl)sulfonyl)piperidin-1-yl)pyridin-3-amine

Tert-butyl carbamate (211.3 mg, 1.804 mmol), sodium tert-butoxide (173.4mg, 1.804 mmol), BrettPhos Pre-catalyst (143.7 mg, 0.1804 mmol) andBrettPhos (96.83 mg, 0.1804 mmol) were degassed by vacuum/nitrogencycles (×5). A solution of1-[[1-(3-chloro-5-fluoro-4-pyridyl)-4-piperidyl]sulfonyl]-4-methyl-piperazine(340 mg, 0.9022 mmol) in dry toluene (9.884 mL) was added and theresulting mixture was heated to 80° C. After 5 minutes at 80° C. thereaction was cooled to RT and partitioned between ethyl acetate andwater. The combined organics was dried with MgSO₄ and concentrated invacuo to a yellow solid. The yellow solid was purified by columnchromatography using 1% MeOH/DCM to elute side products and then 5-10%MeOH/DCM to elute product. Relevant fractions combined and concentratedin vacuo to yield a light yellow solid. It was dissolved in DCM (10 mL)followed by the addition of TFA (1.029 g, 695.3 μL, 9.022 mmol). Themixture was stirred at room temperature for 2 hours. The mixture wasconcentrated in vacuo to yield5-fluoro-4-(4-((4-methylpiperazin-1-yl)sulfonyl)piperidin-1-yl)pyridin-3-amineas a light orange solid. MS (ES+) 358.1.

The following amines were prepared according to methods similar to theone depicted in Procedure N-22

Preparation N-231-((1-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)methyl)-4-methylpiperazin-2-one

Step 1: tert-butyl4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

Methanesulfonyl chloride (186.3 mg, 125.9 μL, 1.626 mmol) was addeddropwise to a stirred solution of tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (350 mg, 1.626 mmol) and DIPEA(222.8 mg, 300.3 μL, 1.724 mmol) in DCM (5 mL) at 0° C. The reactionmixture was allowed to warm to ambient temperature over 16 hours thentreated with water. The phases were separated and the aqueous phaseextracted with DCM (×3). The combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo to give the sub-titlecompound as a white solid (505 mg, >100% Yield) that was used directlyassuming 100% yield and purity. MS (ES+−t-Bu) 238.0.

Step 2: tert-butyl4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate

A 60% dispersion of sodium hydride (84.55 mg, 2.114 mmol) was added to astirred solution of 4-methylpiperazin-2-one (241.3 mg, 2.114 mmol) inDMF (10 mL) and the reaction stirred at ambient temperature for 30minutes. Tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate(477 mg, 1.626 mmol) in DMF (5 mL) was added dropwise and the reactionstirred at ambient temperature for a further 92 hours then at 50° C. fora further 20 hours. The reaction was cooled to ambient temperature,quenched by the addition of water and the mixture extracted with EtOAc(×3). The combined organic extracts were washed with brine (×3), dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (ISCO Companion, 40 g column, eluting with 0 to10% MeOH/DCM, loaded in DCM) to give tert-butyl4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate productas a colourless oil (99 mg, 20% Yield). MS (ES+) 312.2.

Step 3: 4-methyl-1-(piperidin-4-ylmethyl)piperazin-2-one

TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butyl4-[(4-methyl-2-oxo-piperazin-1-yl)methyl]piperidine-1-carboxylate (98mg, 0.3147 mmol) in DCM (2 mL) and the reaction stirred at ambienttemperature for 16 hours. The solvent was removed in vacuo and theresidue azeotroped with DCM (×2) and ether (×2). The residue was passedthrough a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. Theproduct was eluted by washing the cartridge with 2M NH₃ in MeOH/DCMmixtures. The solvent was removed in vacuo to give4-methyl-1-(piperidin-4-ylmethyl)piperazin-2-one as a colourless oil (65mg, 98% Yield). MS (ES+) 212.0.

Step 4: tert-butyl4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

Preparation N-13 was followed. MS (ES+) 322.1

Preparation N-244-(4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-amine

Step 1: tert-butyl4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidine-1-carboxylate

A mixture of 3,3-difluoropyrrolidine (Hydrochloric Acid (1)) (965 mg,6.722 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (1.720 g, 8.066mmol), DIPEA (955.6 mg, 1.288 mL, 7.394 mmol) and crushed 4A MS (965mg,) in DCE (30 mL) were stirred at ambient temperature for 3 hours.NaBH(OAc)₃ (Sodium Ion (1)) (2.848 g, 13.44 mmol) was added and thereaction stirred at ambient temperature for a further 16 hours. Themixture was filter through Celite (washing with DCM) and the filtrateconcentrated in vacuo. The residue was purified by column chromatography(ISCO Companion, 80 g column, eluting with 0 to 10% MeOH/DCM, loaded inDCM) to give tert-butyl4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidine-1-carboxylate as acolourless oil that was deprotected directly assuming 100% yield andpurity. MS (ES+) 305.1.

Step 2: 4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidine

TFA (766.5 mg, 517.9 μL, 6.722 mmol) was added to a stirred solution oftert-butyl4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidine-1-carboxylate (2.046g, 6.722 mmol) in DCM (15 mL) and the reaction stirred at ambienttemperature for 66 hours. The solvent was removed in vacuo and theresidue azeotroped with DCM (×2) and ether (×2). The residue was passedthrough a 50 g SCX-2 cartridge and washed with MeOH/DCM mixtures. Theproduct was eluted by washing the cartridge with 2M NH₃ in MeOH/DCMmixtures. The solvent was removed in vacuo to give4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidine as a pale yellow solid(1.15 g, 84% Yield over 2 steps). MS (ES+) 205.1.

Step 3:4-(4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-amine

Preparation N-1 was followed. MS (ES+) 297.2

Preparation N-254-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)pyridin-3-amine

Step 1: tert-butyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate

To a mixture of tert-butyl 1-oxa-8-azaspiro[2.5]octane-8-carboxylate (1g, 4.689 mmol) and thiourea (356.9 mg, 4.689 mmol) was added water andthe mixture stirred at room temperature for 72 h. the reaction mixturewas partitioned between DCM and water, the organic extract was washedwith brine, dried (MgSO₄) and concentrated to give1-thia-6-azaspiro[2.5]octane-6-carboxylate as a pale yellow oil whichsolidified upon standing. (910 mg, 84%). MS (ES+−t-Bu) 173.9.

Step 2: tert-butyl 4-mercapto-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate(430 mg, 1.875 mmol) in THF (5 mL) was added LiAlH₄ (Lithium Ion (1))(0.9375 mL of 2 M, 1.875 mmol) and the solution was stirred at roomtemperature for 1 h. The reaction was quenched by careful dropwiseaddition of water (2 ml), stirred for 10 mins before the reactionmixture was partitioned between water and EtOAc. The organic extract waswashed with brine, dried (MgSO₄) and concentrated to give tert-butyl4-methyl-4-sulfanyl-piperidine-1-carboxylate as a colorless oil. (380mg, 87%). MS (ES−) 231.0.

Step 3: tert-butyl 4-methyl-4-(methylthio)piperidine-1-carboxylate

To a solution of tert-butyl 4-methyl-4-sulfanyl-piperidine-1-carboxylate(380 mg, 1.642 mmol) in THF (5 mL) cooled to −78° C. was added LiHMDS(1.724 mL of 1 M, 1.724 mmol) and the solution stirred for 10 minsbefore MeI (256.3 mg, 0.1124 mL, 1.806 mmol) was added and the solutionallowed to warm to 0° C. over approximately 1 h. The reaction was thenquenched carefully by the addition of saturated ammonium chloride andextracted into EtOAc. The aqueous was further extracted with EtOAc andthe combined organics were washed with brine, dried (MgSO₄) andconcentrated to give a yellow oil (390 mg, 96%).

Step 4: tert-butyl 4-methyl-4-(methylsulfonyl)piperidine-1-carboxylate

A solution of tert-butyl4-methyl-4-methylsulfanyl-piperidine-1-carboxylate (380 mg, 1.549 mmol)in DCM (15 mL) was cooled to 0° C. and 3-Chloroperoxybenzoic acid (867.8mg, 3.872 mmol) was added portionwise over approx 10 mins. The solutionwas stirred for 30 mins and then allowed to warm to room temperature andstirred for a further 1 h. The reaction was quenched with saturatedsodium hydrogen carbonate (4 ml) and saturated sodium thiosulphate (4ml) and stirred vigorously for 5 mins. The DCM layer was removed and theaqueous further extracted with DCM. The combined organic layers werewashed with saturated sodium carbonate and brine, dried (MgSO₄) andconcentrated to give tert-butyl4-methyl-4-(methylsulfonyl)piperidine-1-carboxylate as a sticky oilwhich solidified upon standing (450 mg, 100%).

Step 5: 4-methyl-4-(methylsulfonyl)piperidine

To a solution of tert-butyl4-methyl-4-methylsulfonyl-piperidine-1-carboxylate (430 mg, 1.550 mmol)in DCM (10 mL) was added TFA (3 mL, 38.94 mmol) and the solution stirredat room temperature for 1 h. The reaction was concentrated andazeotroped twice with DCM to give 4-methyl-4-(methylsulfonyl)piperidineas a sticky oil that was used in next step without further purification.MS (ES+) 178.0.

Step 6: 4-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)pyridin-3-amine

Preparation N-1 was followed. MS (ES+) 270.1

Preparation N-268-(3-aminopyridin-4-yl)-2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazin-1-one

Step 1:2-isopropyl-8-(3-nitropyridin-4-yl)octahydro-1H-pyrazino[1,2-a]pyrazin-1-one

NaH (15.87 mg, 0.3967 mmol) then 2-iodopropane (73.56 mg, 43.19 μL,0.4327 mmol) were added to a solution of2-(3-nitro-4-pyridyl)-3,4,6,7,8,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-9-one(100 mg, 0.3606 mmol) (prepared according to a procedure similar to Step1 of Preparation N-1) in THF (5 mL) under N₂. The reaction mixture wasstirred at reflux for 24 h then it was partitioned between EtOAc and asaturated bicarbonate aqueous solution. Combined organic extract waswashed with brine, dried over MgSO₄ and concentrated in vacuo to producean oil that was used in next step without further purification. MS (ES+)320.1.

Step 2:8-(3-aminopyridin-4-yl)-2-isopropyloctahydro-1H-pyrazino[1,2-a]pyrazin-1-one

Step 2 of Preparation N-1 was followed. MS (ES+) 290.2

Preparation N-27(S)-5-(3-aminopyridin-4-yl)hexahydro-2H-isothiazolo[2,3-a]pyrazine1,1-dioxide Step 1: (S)-tert-butyl4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate

To a solution of tert-butyl(3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.5 g, 11.56 mmol) inDCM (16.25 mL) at 0° C. under a nitrogen atmosphere was added TEA (1.872g, 2.579 mL, 18.50 mmol) and then dropwise MsCl (2.913 g, 1.968 mL,25.43 mmol). The reaction was allowed to warm to ambient temperature andstirred thereat for 18 hours. The suspension was partitioned between DCM(2×50 mL) and water (50 mL). The combined organics were washed withbrine (50 mL), dried (Na₂SO₄) and concentrated in vacuo to afford a palehoney-coloured oil (4.9 g). The residue was purified by columnchromatography on ISCO Companion (ELSD) eluting with DCM (A): Methanol(B) (0-10% (B), 80 g, 16.0 CV, 60 mL/min) to afford a mixture ofproducts (2.3 g). This oily residue was purified again by columnchromatography on ISCO Companion (ELSD) eluting with DCM (A): EthylAcetate (B) (0-50% (B), 40 g, 25.0 CV, 40 mL/min) to afford(S)-tert-butyl4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylateas a colourless oil (1.58 g, 37%). MS (ES+) 317.0.

Step 2: (S)-tert-butyltetrahydro-2H-isothiazolo[2,3-a]pyrazine-5(3H)-carboxylate 1,1-dioxide

To a solution of tert-butyl(3S)-4-methylsulfonyl-3-(methylsulfonyloxymethyl)piperazine-1-carboxylate(500 mg, 1.342 mmol) in anhydrous THF (10 mL) at −78° C. was addeddropwise LiHMDS (1 M in THF) (1.476 mL of 1.0 M, 1.476 mmol). Thereaction mixture was stirred and allowed to slowly reach ambienttemperature over 90 mins and stirred thereat for 18 hours. The reactionwas cooled again to −78° C. and thereto was added dropwise LiHMDS (1 Min THF) (1.476 mL of 1.0 M, 1.476 mmol). The reaction mixture wasstirred and allowed to slowly reach ambient temperature over 90 mins andstirred thereat for a further 2 hours. The reaction was quenched withwater (5 mL) and partitioned between the aqueous and ethyl acetate (3×50mL). The combined organics were dried (Na₂SO₄) and concentrated in vacuoto afford an orange oil (490 mg). The residue was purified by columnchromatography on ISCO Companion (ELSD) eluting with petroleum ether(A): ethyl acetate (B) (0-40% (B), 12 g, 21.0 min, 30 mL/min) to afford(S)-tert-butyltetrahydro-2H-isothiazolo[2,3-a]pyrazine-5(3H)-carboxylate 1,1-dioxideas a pale cream solid (361 mg, 97%). MS (ES+−t-Bu) 221.0

Step 3: (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide

To a solution of tert-butyl(3aS)-1,1-dioxo-2,3,3a,4,6,7-hexahydroisothiazolo[2,3-a]pyrazine-5-carboxylate(360 mg, 1.303 mmol) in DCM (5 mL) at 0° C. was added TFA (1.25 mL,16.22 mmol) dropwise and the reaction was stirred and warmed slowly toambient temperature over 45 mins. The reaction mixture was concentratedin vacuo and the residue was adsorbed onto a pre-wetted (methanol/DCM(1:1), 10 mL) SCX-2 cartridge (10 g) and flushed with DCM/methanol (1:1,50 mL) and then the basic components eluted with 2 M ammonia in methanol(50 mL). The basic eluent was evaporated to dryness to afford(S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide as a colourlessoil (192 mg, 84%).

Step 4:(S)-5-(3-aminopyridin-4-yl)hexahydro-2H-isothiazolo[2,3-a]pyrazine1,1-dioxide

Preparation N-1 was followed. MS (ES+) 269.1

Preparation N-28 4-(3-methyl-4H-1,2,4-triazol-4-yl)pyridin-3-amine

Step 1: 3-bromo-4-isothiocyanatopyridine

3-bromopyridin-4-amine (5 g, 28.90 mmol) was suspended in dry toluene(100 mL) and cooled in an ice-bath. A solution of thiophosgene (6.646 g,4.407 mL, 57.80 mmol) in dry toluene (100 mL) was added dropwise over 25mins. The resulting orange/red suspension was stirred at refluxovernight. The red suspension was allowed to cool to RT and concentratedunder reduced pressure to give a dark brown/red solid. This material waspartitioned between saturated NaHCO₃ and DCM. The aqueous layer wasextracted with further DCM (3×50 mL) and the combined organics weredried over Na₂SO₄, filtered and concentrated under reduced pressure togive a dark red solid/gum. This material was suspended in MeOH/DCM,adsorbed onto silica under reduced pressure and purified by columnchromatography (75% EtOAc in hexanes, ˜300 mL silica) to give3-bromo-4-isothiocyanatopyridine as a red oil which solidified onstanding (3.513 g, 57% Yield). MS (ES+) 216.9.

Step 2: 2-acetyl-N-(3-bromopyridin-4-yl)hydrazinecarbothioamide

3-bromo-4-isothiocyanato-pyridine (1 g, 4.650 mmol) and acetylhydrazine(344.5 mg, 4.650 mmol) were dissolved in dry 1,4-dioxane (10 mL) andstirred at 80° C. for 0.75 hrs. The orange suspension was allowed tocool to RT. The viscous suspension was diluted with ether and the solidwas collected by fitration and washed with ether (3×5 mL) to give2-acetyl-N-(3-bromopyridin-4-yl)hydrazinecarbothioamide as a salmon-pinksolid (1.2187 g, 91% Yield). MS (ES−) 288.9.

Step 3: 4-(3-bromopyridin-4-yl)-5-methyl-4H-1,2,4-triazole-3-thiol

2-acetyl-N-(3-bromopyridin-4-yl)hydrazinecarbothioamide (200 mg, 0.6917mmol) was dissolved in sodium hydrogen carbonate (4 mL,) and stirred at50° C. for 2 hrs and at 100° C. for 5 hrs. The reaction mixture was thenallowed to stand at RT for 48 h before it was carefully neutralised withdilute HCl and partitioned with 10% MeOH in DCM. The aqueous layer wasextracted with further 10% MeOH in DCM (3×10 mL) and the combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure to give4-(3-bromopyridin-4-yl)-5-methyl-4H-1,2,4-triazole-3-thiol as an orangesolid (152.6 mg). MS (ES+) 272.9.

Step 4: 3-bromo-4-(3-methyl-4H-1,2,4-triazol-4-yl)pyridine

4-(3-bromo-4-pyridyl)-5-methyl-1,2,4-triazole-3-thiol (145 mg, 0.5348mmol) was suspended in dry DCM (4 mL) and cooled in an ice-bath. Asolution of hydrogen peroxide (133.5 μL of 30% w/v, 1.177 mmol) in AcOH(1.5 mL) was added slowly dropwise and the resulting mixture was stirredat RT for 2 hrs. The reaction mixture was cooled with an ice bath andquenched by slow addition of 2M NaOH and partitioned with DCM. Theaqueous layer was extracted with further DCM (3×10 mL) and the combinedorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a yellow gum/solid (112.5 mg). This material wasredissolved in MeOH/DCM, adsorbed onto silica under reduced pressure andpurified by column chromatography (7.5% MeOH in DCM, ˜75 mL silica) togive 3-bromo-4-(3-methyl-4H-1,2,4-triazol-4-yl)pyridine as a cream solid(82.3 mg, 64% Yield). MS (ES+) 240.9.

Step 5: 4-(3-methyl-4H-1,2,4-triazol-4-yl)pyridin-3-amine

Procedure similar to Step 3a of Preparation N-14 was used.

Preparation N-29 5-methyl-4-(5-methyl-1H-pyrazol-1-yl)pyridin-3-amine

Step 1: 3-bromo-4-hydrazinyl-5-nitropyridine

A solution of 3-bromo-4-chloro-5-nitro-pyridine (500 mg, 2.106 mmol),hydrazine hydrate (158.1 mg, 153.6 μL, 3.159 mmol) in ethanol (5.000 mL)was stirred at RT for 1 h. The bright yellow precipitate was filtered,washed with methanol and dried under vacuum to leave3-bromo-4-hydrazinyl-5-nitropyridine (390 mg, 79.5%). MS (ES−) 232.8.

Step 2: 3-bromo-4-(5-methyl-1H-pyrazol-1-yl)-5-nitropyridine

2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde (320 mg, 2.459 mmol) and(3-bromo-5-nitro-4-pyridyl)hydrazine (286.4 mg, 1.229 mmol) were heatedunder reflux in ethanol (2.864 mL) overnight. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between DCM and asaturated aqueous sodium hydrogen carbonate solution. Combined organicextract was dried over MgSO₄ and concentrated in vacuo to leave3-bromo-4-(5-methyl-1H-pyrazol-1-yl)-5-nitropyridine as a yellow oil.(200 mg, 85%). MS (ES+) 284.9.

Step 3: 3-methyl-4-(5-methyl-1H-pyrazol-1-yl)-5-nitropyridine

To an oven dried flask under nitrogen was added3-bromo-4-(5-methylpyrazol-1-yl)-5-nitro-pyridine (200 mg, 0.6005 mmol),Pd₂dba₃ (8.249 mg, 0.009008 mmol) and X-Phos (8.590 mg, 0.01802 mmol).Anhydrous THF (1.700 mL) was added, followed by1,4-diazabicyclo[2.2.2]octane; trimethylalumane (153 mg, 0.6005 mmol).The reaction was heated at reflux for 2 hours then cooled to ambienttemperature before it was quenched by the addition of water. The mixturewas extracted with EtOAc (×3) and the combined organic extract waswashed with brine, dried (MgSO₄) and concentrated in vacuo to leave a3/1 mixture of 3-methyl-4-(5-methyl-1H-pyrazol-1-yl)-5-nitropyridine and4-(5-methyl-1H-pyrazol-1-yl)-3-nitropyridine, that was used in the nextstep without further purification. (140 mg of product isolated as amixture). MS (ES+) 219.0.

Step 4: 5-methyl-4-(5-methyl-1H-pyrazol-1-yl)pyridin-3-amine

Reduction was run according to Step 2 of Preparation N-1. MS (ES+)189.0.

Preparation N-305-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-amine

Step 1: 3-bromo-5-fluoro-4-hydrazinylpyridine

3-bromo-4-chloro-5-fluoro-pyridine (500 mg, 2.376 mmol), hydrazine(761.4 mg, 745.7 μL, 23.76 mmol), Na₂CO₃ (503.7 mg, 4.752 mmol) incyclohexanol was heated at 100 C overnight. The reaction mixture wasfiltered on celite and loaded on a SCX column, washed with DCM/MeOHmixtures and was eluted with a 2M solution of NH₃ in MeOH. The filtratewas concentrated in vacuo and the 3/1 mixture of3-bromo-5-fluoro-4-hydrazinylpyridine and3-bromo-4-chloro-5-hydrazinylpyridine was used in next step withoutfurther purification. MS (ES+) 205.9.

Step 2: 3-bromo-5-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)pyridine

Acetamide (136.7 mg, 2.315 mmol), 1,1-dimethoxy-N,N-dimethyl-methanamine(382.0 mg, 425.9 μL, 3.206 mmol), in dioxane was heated at 45-50° C.under 150 mm Hg vacuum for 2 h. The reaction mixture was concentrated invacuo. To the residue, (3-bromo-5-fluoro-4-pyridyl)hydrazine (367 mg,1.781 mmol) and dioxane-acetic acid (1/1) was added and the mixture washeated at 130° C. for 1 h then at 160° C. for 2 h. At RT, the residuewas loaded on a SCX column, washed with MeOH/DCM mixture. The filtrateis concentrated in vacuo yielding pure3-bromo-5-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)pyridine as a darkoil. MS (ES+) 257.0.

Step 3: 5-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-amine

Amination reaction was run according to a procedure similar as Step 3 ofPreparation N-14. MS (ES+) 194.0.

Preparation N-31 tert-butyl piperidine-4-carboxylate

Step 1: O1-benzyl O4-tert-butyl piperidine-1,4-dicarboxylate 21

In a 5 L flange flask was charged1-benzyloxycarbonylpiperidine-4-carboxylic acid 20 (200 g, 759.6 mmol)in DCM (500.0 mL) followed by additional DCM (2.000 L), t-butanol (140.8g, 181.7 mL, 1.899 mol) and DMAP (46.40 g, 379.8 mmol). The mixture wascooled on ice/salt/water bath (internal −3.4° C.).3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (HydrochloricAcid (1)) (145.6 g, 759.6 mmol) was added portionwise over 15 mins, withaddition funnel rinsed with DCM (500.0 mL). Mixture was stirred on icebath for approx. 2 h. Ice bath was then removed (internal 3° C.) andallowed to warm to room temperature overnight. Mixture was washed with5% citric acid (2×500 mL), then saturated NaHCO₃ (500 mL), water (500mL), and organics dried over MgSO₄, which was then filtered andconcentrated in vacuo to leave product 21 as a viscous light yellow oilwhich turned to a white solid on standing. (246.1 g, 101%). ¹H NMR (500MHz, DMSO-d6) δ 7.40-7.31 (m, 5H), 5.08 (s, 2H), 3.90 (dt, 2H), 2.93 (brs, 2H), 2.43 (tt, 1H), 1.80-1.76 (m, 2H) and 1.45-1.37 (m, 11H).

Step 2: tert-butyl piperidine-4-carboxylate 22

To a 3 L florentine under nitrogen was charged Pd on C, wet, Degussa(10% Pd, 50% WATER) (8.120 g, 76.30 mmol) then EtOAc (1.706 L). Themixture was degassed via N₂/vacuum cycles (3×), then a solution ofO1-benzyl 04-tert-butyl piperidine-1,4-dicarboxylate 21 (243.7 g, 763.0mmol) in EtOAc (243.7 mL) was added. Mixture was stirred under ahydrogen atmosphere overnight. Hydrogen was replenished and mixture wasstirred for a further 3.5 h. Methanol (60 mL) was added to aiddissolution of precipitate then filtered through celite, washing throughwith methanol. Filtrate concentrated in vacuo to leave a brown oil witha slight suspension of a white solid, 138.6 g. Solid removed byfiltration, and washed with minimal EtOAc. Filtrate was concentrated invacuo to leave desired product as a light brown oil (129 g, 91%). ¹H NMR(500 MHz, DMSO-d6) δ 2.88 (dt, 2H), 2.44 (td, 2H), 2.23 (tt, 1H),1.69-1.64 (m, 2H) and 1.41-1.33 (m, 11H).

Preparation N-32 1-(oxetan-3-yl)piperazine

Step 1: benzyl 4-(oxetan-3-yl)piperazine-1-carboxylate 24

Benzyl piperazine-1-carboxylate 23 (27.3 mL, 142.2 mmol) was dissolvedin dry THF (313.1 mL) and oxetan-3-one (12.29 g, 10.93 mL, 170.6 mmol)was added. The resulting solution was cooled in an ice-bath. NaBH(OAc)₃(59.99 g, 284.4 mmol) was added portionwise over 30 mins, about aquarter was added. Mixture removed from ice bath, allowed to warm toroom temperature then continued adding the NaBH(OAc)₃ portionwise over30 mins. On complete addition, an exotherm from 22° C. slowly to 32° C.was observed, whereby the mixture was subsequently cooled on an ice bathuntil an internal of 22° C. was reached. The ice bath was removed andthe reaction mixture's internal temp was steady at 22° C. The mixturewas stirred at room temperature overnight.

The resulting white suspension was quenched by addition of 2M sodiumcarbonate solution (approx 150 mL) (pH=8) and concentrated under reducedpressure to remove THF. Product was then extracted with EtOAc (3×250mL). Organics were combined, dried over MgSO₄, filtered and concentratedunder reduced pressure to leave product 24 as a white solid (32.7 g 83%yield). ¹H NMR (500 MHz, DMSO-d6) δ 7.39-7.30 (m, 5H), 5.07 (s, 2H),4.52 (t, 2H), 4.42 (t, 2H), 3.43-3.39 (m, 5H) and 2.22 (t, 4H). MS (ES+)276.8.

Step 2: 1-(oxetan-3-yl)piperazine 25

In a 1 L florentine was added Pd(OH)₂ (1.661 g, 2.366 mmol) undernitrogen. MeOH (130.8 mL) and EtOAc (261.6 mL) were added and themixture degassed via vacuum/nitrogen cycles (3×). Benzyl4-(oxetan-3-yl)piperazine-1-carboxylate 24 (32.7 g, 118.3 mmol) was thenadded and the mixture stirred under a hydrogen atmosphere over theweekend. Mixture was filtered through a pad of celite, washing throughwith EtOAc then methanol. Filtrate was concentrated in vacuo to leaveproduct 25 as an orange oil 1 (8.1 g, quantitative yield). ¹H NMR (500MHz, DMSO-d6) δ 4.51 (t, 2H), 4.41 (t, 2H), 3.36-3.30 (masked signal,1H), 2.69 (t, 4H) and 2.14 (br s, 4H).

The following compounds were successfully prepared using a proceduresimilar to Example 1 or Examples 3a-3e:

-   2-amino-6-fluoro-N-(4-(4-isopropylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-4);-   2-amino-N-(5-cyclopropyl-4-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-5);-   2-amino-N-(5-chloro-4-(8-methylhexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-6);-   N-(4-(1H-imidazol-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-7);-   2-amino-6-fluoro-N-(4-(4-(2-(methylamino)ethyl)-1H-pyrazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-8);-   2-amino-N-(4-(4-(2-(dimethylamino)ethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-9);-   (R)-2-amino-6-fluoro-N-(4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-10);-   2-amino-6-fluoro-N-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-11);-   (S)-2-amino-6-fluoro-N-(4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-12);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-13);-   2-amino-6-chloro-N-(5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-14);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-15);-   2-amino-6-fluoro-N-(5-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-16);-   2-amino-N-(4-(4-ethylpiperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-17);-   N-(4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-18);-   (R,S)-2-amino-6-fluoro-N-(4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-19);-   2-amino-6-fluoro-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-20);-   (S)-2-amino-6-fluoro-N-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-21);-   2-amino-6-fluoro-N-(4-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-22);-   (R)-2-amino-6-fluoro-N-(4-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-23);-   (S)-2-amino-6-fluoro-N-(4-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-24);-   2-amino-6-chloro-N-(4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-25);-   N-(4-(1H-pyrazol-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-26);-   2-amino-6-fluoro-N-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-27);-   2-amino-6-fluoro-N-(4-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-28);-   N-(4-(1H-imidazol-1-yl)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-29);-   2-amino-6-fluoro-N-(4-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-30);-   2-amino-6-fluoro-N-(4-(5-(oxetan-3-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-31);-   2-amino-N-(5-cyclopropyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-32);-   2-amino-N-(4-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-33);-   2-amino-N-(4-(4-(tert-butyl)piperazin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-34);-   2-amino-6-chloro-N-(4-((3S,4S)-4-(dimethylamino)-3-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-35);-   2-amino-6-chloro-N-(4-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-36);-   2-amino-6-chloro-N-(4-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-37);-   2-amino-6-chloro-N-(4-(4-isopropylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-39);-   2-amino-6-chloro-N-(4-(3-(dimethylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-40);-   2-amino-6-chloro-N-(5-chloro-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-41);-   2-amino-6-chloro-N-(4-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-42);-   2-amino-6-chloro-N-(4-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-43);-   2-amino-6-chloro-N-(4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-44);-   2-amino-6-chloro-N-(4-(4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-45);-   2-amino-6-chloro-N-(4-(4-((dimethylamino)methyl)-4-methoxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-46);-   2-amino-6-chloro-N-(4-(3-(methoxymethyl)-4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-47);-   2-amino-6-chloro-N-(4-(4-cyclobutylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-48);-   2-amino-6-chloro-N-(4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-49);-   2-amino-N-(6-amino-4-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-50);-   2-amino-6-chloro-N-(4-(4-ethylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-51);-   2-amino-6-chloro-N-(6-chloro-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-52);-   2-amino-6-chloro-N-(4-(3,3,4-trimethylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-53);-   2-amino-6-chloro-N-(4-(3,4-dimethylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-54);-   2-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-55);-   N-(4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-56);-   2-amino-6-chloro-N-(5-methyl-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-57);-   2-amino-6-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-58);-   2-amino-6-chloro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-59);-   2-amino-6-chloro-N-(4-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-60);-   2-amino-6-chloro-N-(4-(8-methylhexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-61);-   2-amino-6-fluoro-N-(4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-62);-   2-amino-6-chloro-N-(4-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-63);-   2-amino-6-chloro-N-(4-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-64);-   (R)-2-amino-6-chloro-N-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-65);-   2-amino-6-chloro-N-(4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-66);-   2-amino-6-chloro-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-67);-   2-amino-6-chloro-N-(4-(1-oxidothiomorpholino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-68);-   2-amino-6-chloro-N-(4-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-69);-   2-amino-6-chloro-N-(4-(3-(trifluoromethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-70);-   (S)-2-amino-6-chloro-N-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-71);-   2-amino-6-chloro-N-(4-(2,4-dimethylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-72);-   2-amino-6-chloro-N-(4-(4-methoxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-73);-   methyl-1-(3-(2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)piperidine-4-carboxylate    (Compound I-N-74);-   2-amino-6-chloro-N-(4-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-75);-   2-amino-6-(2-cyanopropan-2-yl)-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-76);-   2-amino-6-(cyanomethyl)-N-(4-(pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-77);-   2-amino-6-(1-cyanoethyl)-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-78);-   2-amino-N-(4-(azepan-1-yl)pyridin-3-yl)-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-79);-   2-amino-6-(cyanomethyl)-N-(5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-80);-   2-amino-6-(cyanomethyl)-N-(4-morpholinopyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-81);-   2-amino-6-(cyanomethyl)-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-82);-   2-amino-6-(cyanomethyl)-N-(4-(4-hydroxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-83);-   2-amino-6-(cyanomethyl)-N-(4-(piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-84);-   2-amino-N-(5-chloro-4-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-85);-   2-amino-N-(5-(difluoromethyl)-4-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-111)    2-amino-6-fluoro-N-(4-(5-(oxetan-3-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-112);-   2-amino-6-fluoro-N-(5-fluoro-4-(8-methylhexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-114);-   (S)-2-amino-6-fluoro-N-(4-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-115);-   (R)-2-amino-6-fluoro-N-(4-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-116);-   2-amino-6-chloro-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-117);-   (S)-2-amino-6-fluoro-N-(5-fluoro-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-125);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-127);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(quinuclidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-130);-   2-amino-6-fluoro-N-(4-(1-methyl-9-oxa-1,4-diazaspiro[5.5]undecan-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-133);-   (R)-2-amino-6-fluoro-N-(5-fluoro-4-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-135);-   2-amino-6-fluoro-N-(4-(4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-136);-   (S)-2-amino-6-fluoro-N-(5-fluoro-4-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-137);-   2-amino-6-(2-cyanopropan-2-yl)-N-(5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-138);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-139);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-140);-   2-amino-6-fluoro-N-(4-morpholinopyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-141);-   2-amino-6-(2-cyanopropan-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-142);-   2-amino-6-(1-cyanoethyl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-143);-   2-amino-6-(1-cyanoethyl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-144);-   2-amino-6-(2-cyanopropan-2-yl)-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-145);-   2-amino-N-(4-(4-(N,N-dimethylsulfamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-146);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-147);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(N-methyl-N-(1-methylpiperidin-4-yl)    sulfamoyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-148);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-149);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-150);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methyl-2-oxopiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-151);-   2-amino-6-fluoro-N-(4-(piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-152);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(morpholinosulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-155);-   2-amino-6-fluoro-N-(4-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-161);-   2-amino-6-fluoro-N-(4-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-162);-   2-amino-6-fluoro-N-(5-fluoro-4-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-163);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(methylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-165);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((4-methylpiperazin-1-yl)sulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-166);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(2-(pyrrolidin-1-yl)ethoxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-167);-   2-amino-N-(4-(4-(azetidin-1-ylsulfonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-169);-   2-amino-6-fluoro-N-(4-(4-(morpholinosulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-170);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((4-methyl-3-oxopiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-171);-   2-amino-6-(1-cyanocyclopropyl)-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-180);-   (R)-2-amino-6-fluoro-N-(5-fluoro-4-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-182);-   2-amino-6-fluoro-N-(4-(4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-183);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(thiazol-2-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-184);-   (R)-2-amino-6-fluoro-N-(5-fluoro-4-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-186);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(2-(pyrrolidin-1-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-187);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-morpholinopiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-189);-   2-amino-6-fluoro-N-(4-(4-(methylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-190);-   2-amino-6-fluoro-N-(5-fluoro-4-(3-(4-methylpiperazine-1-carbonyl)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-191);-   2-amino-6-(1-cyanocyclopropyl)-N-(5-fluoro-4-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-192);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-193);-   N-(4-(4-(1,4-diazabicyclo[3.2.2]nonan-4-ylsulfonyl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-196);-   2-amino-N-(4-(4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-197);-   2-amino-6-fluoro-N-(4-(4-(oxetan-3-ylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-200);-   2-amino-N-(4-(2-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-202);-   2-amino-6-fluoro-N-(4-(4-((2-methoxyethyl)sulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-208);-   2-amino-6-fluoro-N-(4-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-209);-   2-amino-N-(4-(1,1-dioxidothiomorpholino)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-210);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-methyl-3-oxopiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-212);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-213);-   2-amino-6-fluoro-N-(4-(4-((methylsulfonyl)methyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-215);-   2-amino-6-fluoro-N-(4-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-216);-   (S)-2-amino-6-fluoro-N-(4-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-217);-   2-amino-N-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-218);-   2-amino-6-fluoro-N-(4-(2-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-219);-   2-amino-N-(4-(2,2-dimethylpyrrolidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-220);-   2-amino-6-fluoro-N-(4-(3-(methylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-221);-   2-amino-6-fluoro-N-(4-(4-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-222);-   2-amino-6-fluoro-N-(4-(5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-223);-   2-amino-6-fluoro-N-(4-((3aR,7aR)-2-methyl-3-oxohexahydro-1H-pyrrolo[3,4-c]pyridin-5(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-224);-   2-amino-6-fluoro-N-(4-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-225);-   N-(4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-226);-   2-amino-6-fluoro-N-(5-fluoro-4-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-229);-   2-amino-6-fluoro-N-(4-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-230);-   2-amino-6-fluoro-N-(4-(2-methyl-3-oxo-2,9-diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-231);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-232);-   2-amino-6-fluoro-N-(4-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-233);-   4-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)-N,N-dimethylmorpholine-2-carboxamide    (Compound I-N-234);-   2-amino-6-fluoro-N-(4-(1-methyl-2-oxo-1,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-235);-   2-amino-6-fluoro-N-(4-(2-methyl-3-oxo-2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-236);-   2-amino-6-fluoro-N-(4-(3-oxotetrahydro-1H-oxazolo[3,4-a]pyrazin-7(3H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-238);-   2-amino-6-fluoro-N-(5-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-239);-   2-amino-6-fluoro-N-(5-fluoro-4-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-240);-   N-(4-(4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-241);-   2-amino-6-fluoro-N-(5-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-242);-   2-amino-6-fluoro-N-(4-(4-methyl-4-(methylsulfonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-243);-   2-amino-6-fluoro-N-(4-(6-oxohexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-244);-   2-amino-6-fluoro-N-(4-(8-isopropyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-245);-   2-amino-6-fluoro-N-(5-fluoro-4-(pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-246);-   (S)-2-amino-N-(4-(1,1-dioxidotetrahydro-2H-isothiazolo[2,3-a]pyrazin-5(3H)-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-247);-   (S)-2-amino-6-fluoro-N-(5-fluoro-4-(3-oxotetrahydro-1H-oxazolo[3,4-a]pyrazin-7(3H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-248);-   2-amino-N-(4-(1,1-dioxidothiomorpholino)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-250);-   2-amino-N-(4-(2,2-dimethyl-1,1-dioxidothiomorpholino)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-252);-   N-(4-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-253);-   2-amino-6-fluoro-N-(4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-256);-   (R)-2-amino-6-fluoro-N-(4-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-258);-   2-amino-6-fluoro-N-(1-methyl-1H-pyrrolo[3,2-a]pyridin-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-259);-   2-amino-6-fluoro-N-(4-(4-(4-methyl-1,2,5-oxadiazol-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-260);-   2-amino-6-fluoro-N-(4-(3-methyl-4H-1,2,4-triazol-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-263);-   2-amino-N-(4-(azepan-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-264);-   2-amino-6-fluoro-N-(4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-265);-   2-amino-6-fluoro-N-(4-(4-methoxypiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-266);-   2-amino-N-(4-(4-((dimethylamino)methyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-267);-   N-(4-(4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-268);-   2-amino-N-(4-(4,5-dimethyl-1H-imidazol-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-269);-   2-amino-6-fluoro-N-(5-fluoro-4-(piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-270);-   2-amino-N-(4-(4-(azetidin-1-ylsulfonyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-271);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-272);-   N-(4-(4-(1,4-diazabicyclo[3.2.2]nonan-4-ylsulfonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-273);-   2-amino-6-fluoro-N-(5-fluoro-4-(6-oxohexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-277);-   (S)-2-amino-6-fluoro-N-(5-fluoro-4-(6-oxohexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-279);-   (R)-2-amino-6-fluoro-N-(5-fluoro-4-(6-oxohexahydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-280);-   2-amino-N-(5-chloro-4-(pyrrolidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-281);-   2-amino-6-fluoro-N-(4-(4-(methoxymethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-282);-   2-amino-6-fluoro-N-(4-(5-methyl-1H-imidazol-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-283);-   2-amino-N-(5-chloro-4-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-284);-   (R)-2-amino-N-(5-chloro-4-(3-cyanopyrrolidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-285);-   2-amino-N-(5-chloro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-286);-   2-amino-N-(5-chloro-4-(3-(methylsulfonyl)pyrrolidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-287);-   N-(4-(4-(1H-imidazol-1-yl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-288)    2-amino-6-fluoro-N-(5-fluoro-4-(3-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-289);-   2-amino-N-(4-(3-(dimethylcarbamoyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-290);-   2-amino-6-fluoro-N-(5′-methoxy-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-82);-   2-amino-6-fluoro-N-(4-(1-(2-methoxyethyl)-1H-imidazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-83);-   2-amino-N-(4-cyclopropyl-5-methoxypyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-84);-   2-amino-6-fluoro-N-(4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-1);-   2-amino-N-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-2);-   2-amino-N-(5-chloro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-3);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-4);-   2-amino-6-chloro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-5);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methyl-1,4-diazepane-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-6);-   N-(4-(4-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-7);-   2-amino-N-(4-(4-(4-cyclopropylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-13);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3,3,4-trimethylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-15);-   2-amino-N-(4-(4-cyano-4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-25);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-methyl-4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-54);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(5-methyl-2,5-diazabicyclo[4.1.0]heptane-2-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-65); and-   N-(4-(4-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)piperidin-1-yl)-5-chloropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-66).

The following compounds were prepared according to methods similar tothe one depicted in the procedure described in Example 2:

-   2-amino-N-(4-(4-aminopiperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-86);-   2-amino-6-chloro-N-(4-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-87);-   2-amino-6-chloro-N-(4-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-88);-   2-amino-6-(cyanomethyl)-N-(4-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-89);-   2-amino-N-(4-(2-(aminomethyl)morpholino)pyridin-3-yl)-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-90);-   2-amino-N-(4-(4-(aminomethyl)piperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-91);-   2-amino-6-fluoro-N-(5-fluoro-4-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-118);-   2-amino-N-(5-chloro-4-(piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-126);-   2-amino-6-fluoro-N-(6-(methylamino)-4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-129); and-   N-(4-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-255).

Example 42-amino-N-(4-(4-(4-ethylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(compound I-G-9)

Step 1:1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylicacid (Compound I-N-92)

tert-butyl1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)piperidine-4-carboxylateprepared according to methods similar to the one depicted in Example 1was dissolved in DCM (5 mL). TFA (1 mL, 12.98 mmol) was added and themixture was stirred at RT for 5 hr. The reaction mixture wasconcentrated to give1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylicacid as a beige solid that was used in next step without furtherpurification. MS (ES+) 418.1.

Step 2:2-amino-N-(4-(4-(4-ethylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)piperidine-4-carboxylicacid (Trifluoroacetic Acid (2)) (30 mg,),(benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium (BoronTetrafluoride Ion (1)) (46.17 mg, 0.1438 mmol) and TEA (33.07 mg, 45.55μL, 0.3268 mmol) in DMF was stirred at room temperature for 5 minutesfollowed by the addition of 1-ethylpiperazine (13.68 mg, 0.1198 mmol).The mixture was stirred at room temperature for 1 hour. The mixture wasfiltered and purified directly by fractionlynx yielding2-amino-N-(4-(4-(4-ethylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide.yield 38% MS (ES+) 514.0.

The following compounds were successfully prepared using a proceduresimilar to Example 4:

-   2-amino-N-(4-(4-(azetidine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-8);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-10);-   (R)-2-amino-N-(4-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-11);-   N-(4-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-14);-   2-amino-N-(4-(4-((3-(dimethylamino)propyl)(methyl)carbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-16);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(5-methyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-18);-   2-amino-N-(4-(4-(tert-butylcarbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-19);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((1-methylpiperidin-4-yl)carbamoyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-20);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-methoxyazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-21);-   2-amino-N-(4-(4-(3-(dimethylamino)azetidine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-22);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((1-methylazetidin-3-yl)carbamoyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-23);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((1-methylpyrrolidin-3-yl)carbamoyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-24);-   2-amino-N-(4-(4-((3-(dimethylamino)propyl)carbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-26);-   2-amino-N-(4-(4-(dimethylcarbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-29);-   2-amino-N-(4-(4-((2-(dimethylamino)ethyl)carbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-30);-   2-amino-N-(4-(4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-31);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-(oxetan-3-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-32);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(methylcarbamoyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-33);-   2-amino-N-(4-(4-(4-cyclobutylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-35);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(morpholine-4-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-36);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(oxetan-3-ylcarbamoyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-37);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methyl-4,7-diazaspiro[2.5]octane-7-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-38);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((2-methoxyethyl)(methyl)carbamoyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-40);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-hydroxyazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-41);-   2-amino-N-(4-(4((2-(azetidin-1-yl)ethyl)carbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-42);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-43);-   N-(4-(4-(1,4-diazabicyclo[3.2.1]octane-4-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-46);-   (S)-2-amino-N-(4-(4-(3,4-dimethylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-47);-   N-(4-(4-([1,3′-biazetidine]-1′-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-49);-   (R)-2-amino-N-(4-(4-(3,4-dimethylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-50);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-52);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-53);-   2-amino-6-fluoro-N-(5-methyl-4-(4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-55);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-(piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-57);-   (S)-N-(4-(4-([1,3′-bipyrrolidine]-1′-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-58);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-59);-   N-(4-(4-([1,4′-bipiperidine]-1′-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-60);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-hydroxy-3-methylazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-63);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-64);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-fluoroazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-67);-   2-amino-N-(4-(4-(4-(azetidin-1-yl)piperidine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-68);-   N-(4-(4-(1,4-diazabicyclo[3.2.1]octane-4-carbonyl)piperidin-1-yl)-5-chloropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-69);-   N-(4-(4-((5S)-1,4-diazabicyclo[3.2.1]octane-4-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-70);-   N-(4-(4-((5R)-1,4-diazabicyclo[3.2.1]octane-4-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-71);-   N-(4-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-72);-   2-amino-N-(4-(4-(3,3-difluoroazetidine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-73);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-fluoroazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-74);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-methoxy-3-methylazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-75);-   2-amino-N-(4-(4-(3-cyanoazetidine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-76);-   2-amino-N-(4-(4-(azetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-77);-   2-amino-6-fluoro-N-(4-(4-(3-methoxyazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-78);-   2-amino-6-fluoro-N-(4-(4-(3-methoxy-3-methylazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-79);-   2-amino-N-(4-(4-(3,3-difluoroazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-80);-   2-amino-N-(4-(4-(3-cyanoazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-81);-   2-amino-6-fluoro-N-(4-(4-(3-fluoroazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-82);-   2-amino-6-fluoro-N-(4-(4-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-83);-   N-(4-(4-(2-oxa-6-azaspiro[3.4]octane-6-carbonyl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-84);-   2-amino-6-fluoro-N-(4-(4-(morpholine-4-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-85);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-(methylsulfonyl)azetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-86);-   N-(4-(4-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-87);-   N-(4-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-88);-   2-amino-6-fluoro-N-(4-(4-(3-(methylsulfonyl)azetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-89);-   N-(4-(4-(1-oxa-6-azaspiro[3.3]heptane-6-carbonyl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-90);-   2-amino-N-(4-(4-(3-ethoxyazetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-91);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-(3-methyloxetan-3-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-92);-   (R)-2-amino-6-fluoro-N-(4-(4-(3-methoxypyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-93);-   (S)-2-amino-6-fluoro-N-(4-(4-(3-methoxypyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-94);-   4-(1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carbonyl)-1-methylpiperazine    1-oxide (Compound I-G-95);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-(1-methylazetidin-3-yl)piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-96);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-(methoxymethyl)azetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-98); and-   (S)-2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-methoxypyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-99).

Example 52-amino-6-fluoro-N-(5-fluoro-4-(4-(piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-G-12)

tert-butyl4-(1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carbonyl)piperazine-1-carboxylateprepared using procedure similar to Example 4 was dissolved in a mixtureof DCM (5 mL)/TFA (1 mL, 12.98 mmol) and stirred at RT for 90 min. thenconcentrated in vacuo. The residue was purified by fractionlynx. Cleanfractions were freeze dried to yield2-amino-6-fluoro-N-(5-fluoro-4-(4-(piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.MS (ES+) 486.2.

The following compounds were successfully prepared using a proceduresimilar to Example 5:

-   2-amino-N-(4-(4-(3,3-dimethylpiperazine-1-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-27);-   N-(4-(4-(4,7-diazaspiro[2.5]octane-7-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-28);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-(methylamino)azetidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-34);-   N-(4-(4-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-44);-   (R)-2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-45);-   2-amino-N-(5-chloro-4-(4-(piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-48);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-51);-   2-amino-6-fluoro-N-(5-methyl-4-(4-(piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-56);-   (S)-2-amino-6-fluoro-N-(5-fluoro-4-(4-(3-methylpiperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-61); and-   N-(4-(4-(2,5-diazabicyclo[4.1.0]heptane-2-carbonyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-G-62).

Example 62-amino-N-(4-(4-(azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-93)

Step 1:2-amino-6-chloro-N-(4-(4-oxopiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of2-amino-6-chloro-N-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(prepared according to a procedure similar to Example 1) (420 mg, 0.9771mmol) in tetrahydrofuran (10 mL) was added HCl (4.886 mL of 2 M, 9.771mmol). The resulting mixture was stirred at room temperature overnight.The resulting reaction mixture was diluted with water (100 mL), madebasic with 2.5 N aqueous sodium hydroxide, and extracted three timeswith dichloromethane (100 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure to give2-amino-6-chloro-N-(4-(4-oxopiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a pale yellow solid which was used without further purification. MS(ES+) 386.1.

Step 2:2-amino-N-(4-(4-(azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of2-amino-6-chloro-N-[4-(4-oxo-1-piperidyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.1296 mmol), azetidine (Hydrochloric Acid (1)) (12.12 mg,0.1296 mmol) and ammonium formate (8.172 mg, 0.1296 mmol) in toluene washeated at reflux for 1 h with a Dean-Stark apparatus. The reaction wascooled to room temperature and evaporated. The resulting yellow solidwas dissolved in DMSO and purified by fractionlynx to yield2-amino-N-(4-(4-(azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. (27 mg, 31%). MS (ES+) 427.2.

The following compounds were successfully prepared using a proceduresimilar to Example 6:

-   2-amino-6-chloro-N-(4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-94);-   2-amino-6-chloro-N-(4-(4-(3-methoxypyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-95);-   N-(4-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-96);-   2-amino-6-chloro-N-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-97);-   (R)-2-amino-6-chloro-N-(4-(4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-98);-   N-(4-(4-(2-oxa-6-azaspiro[3.4]octan-6-yl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-99);-   2-amino-6-chloro-N-(4-(4-(1-oxidothiomorpholino)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-100);-   2-amino-6-chloro-N-(4-(4-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-101);-   2-amino-6-chloro-N-(4-(4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-102);-   (S)-2-amino-6-chloro-N-(4-(4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-103);-   2-amino-6-chloro-N-(4-(4-morpholinopiperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-104);-   2-amino-6-chloro-N-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-105);-   2-amino-6-chloro-N-(4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-106);-   2-amino-6-chloro-N-(4-(4-(3-methoxyazetidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-107);-   2-amino-6-chloro-N-(4-(4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-108); and-   N-(4-(4-(6-oxa-1-azaspiro[3.3]heptan-1-yl)piperidin-1-yl)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-109).

Example 72-amino-N-(5-chloro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-110)

To a solution of2-amino-N-(5-chloro-4-(piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(51 mg, 0.13 mmol) (synthesized according to a procedure similar toExample 2) in THF (4 mL) was added oxetan-3-one (14.31 mg, 11.63 μL,0.1986 mmol) and triacetoxyborohydride (Sodium Ion (1)) (56.12 mg,0.2648 mmol), and the mixture was stirred at rt for 4 h. The reactionmixture was partitioned between an aqueous saturated solution of NaHCO₃and ethyl acetate. The organic extract was washed with brine, dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby fractionlynx to yield2-amino-N-(5-chloro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide.MS (ES+) 447.2.

The following compounds were synthesized according to a proceduresimilar to Example 7:

-   2-amino-N-(5-chloro-4-(8-(oxetan-3-yl)hexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-38);-   (R)-2-amino-N-(5-cyclopropyl-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-119);-   (S)-2-amino-N-(5-cyclopropyl-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-120);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-121);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-122);-   2-amino-6-fluoro-N-(5-methyl-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-123); and-   2-amino-N-(5-chloro-4-(4-(tetrahydrofuran-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-124).

Example 82-amino-6-fluoro-N-(5-fluoro-4-(4-(1-methylpiperidine-4-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-128)

A microwave vial was charged with2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(79 mg, 0.2110 mmol) (synthesized according to a procedure similar toExample 2), 1-methylpiperidine-4-carboxylic acid (Hydrochloric Acid (1))(37.90 mg, 0.2110 mmol), TBTU (74.52 mg, 0.2321 mmol), Et₃N (46.97 mg,64.70 μL, 0.4642 mmol) in NMP (0.5 mL), the tube sealed and stirred at100° C. overnight. The mixture was cooled to RT and was loaded into aMeOH pre-washed SCX column, rinsed with MeOH and released withmethanolic ammonia. The ammonia extracts were concentrated under reducedpressure to give 110 mg of a brown oil/gum, which was purified byFraction Lynx reverse phase column chromatography. The clean fractionswere combined and freeze dried, yielding2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-methylpiperidine-4-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.MS (ES+) 500.2.

The following compounds were synthesized according to a proceduresimilar to Example 8:

-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(quinuclidine-4-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-134);-   2-amino-N-(4-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-153);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-methylpyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-156);-   (S)-2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-methylpyrrolidine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-157);-   2-amino-N-(4-(4-(2-(azetidin-1-yl)acetyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-160);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-methylpiperidine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-173);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylmorpholine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-174);-   (R)-2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-methylpyrrolidine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-181);-   2-amino-N-(4-(4-(1-ethylpyrrolidine-2-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-185);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(2-(pyrrolidin-1-yl)acetyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-187);-   (S)-2-amino-6-fluoro-N-(4-(4-(1-methylpyrrolidine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-198);-   (R)-2-amino-6-fluoro-N-(4-(4-(1-methylpyrrolidine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-199);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(octahydroindolizine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-203);-   2-amino-N-(4-(4-(1-ethylpiperidine-2-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-204);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-isopropylpyrrolidine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-205);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-isopropylpyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-206);-   2-amino-N-(4-(4-(1-ethylpyrrolidine-3-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-207);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-(oxetan-3-yl)piperidine-4-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-211);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(1-methylpiperidine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-214);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylmorpholine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-227);-   2-amino-6-fluoro-N-(4-(4-(oxetane-3-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-254);-   N-(4-(2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-251);-   N-(4-(4-acetylpiperazin-1-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-254);-   N-(4-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-257);-   methyl-4-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperazine-1-carboxylate    (Compound I-N-261);-   N-(4-(1-acetyl-1,8-diazaspiro[4.5]decan-8-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-262);-   N-(4-(1-acetylpiperidin-4-yl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-69);-   2-amino-N-(4-(1-(cyclopropanecarbonyl)piperidin-4-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-70);-   2-amino-N-(4-(1-(1-cyanocyclopropanecarbonyl)piperidin-4-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-71);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(tetrahydrofuran-3-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-274);-   N-(4-(4-acetylpiperazin-1-yl)-5-fluoropyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-275);-   2-amino-N-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-276); and-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(oxetane-3-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-278).

Example 92-amino-N-(4-(4-(azetidine-3-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-168)

Tert-butyl3-(4-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperazine-1-carbonyl)azetidine-1-carboxylate(73 mg, 0.1309 mmol) (prepared using a procedure similar to Example 8)was dissolved in DCM (219.0 μL). TFA (298.5 mg, 201.7 μL, 2.618 mmol)was added and the mixture was stirred at RT for 2 hr. The reactionmixture was concentrated in vacuo and the residue was purified byfractionlynx yielding2-amino-N-(4-(4-(azetidine-3-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamideas a cream solid. MS (ES+) 458.1.

The following compounds were synthesized according to the proceduresimilar to Example 9:

-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(morpholine-2-carbonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-172).

Example 102-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-158)

Tetrahydropyran-4-sulfonyl chloride (16.28 mg, 0.08815 mmol) was addedto a suspension of2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(30 mg, 0.08014 mmol) (synthesized according to the procedure similar toExample 2) and Et₃N (12.16 mg, 16.75 μL, 0.1202 mmol) in DMF (0.2 mL).The crude mixture was purified by Fractionlynx HPLC. The clean aqueousfractions were combined and lyophilised, yielding2-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.MS (ES+) 523.1.

The following compounds were synthesized according to methods similar tothe one depicted in the procedure described in Example 10:

-   2-amino-N-(4-(4-(cyclopropylsulfonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-159);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-((1-methylpiperidin-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-175);-   2-amino-N-(4-(4-(cyclopropylsulfonyl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-176);-   2-amino-6-fluoro-N-(4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-177);-   2-amino-6-fluoro-N-(4-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-178);-   2-amino-6-fluoro-N-(4-(4-((tetrahydrofuran-3-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-179);-   2-amino-6-fluoro-N-(4-(4-((1-methylpiperidin-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-188);-   2-amino-6-fluoro-N-(4-(4-(oxetan-3-ylsulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-195); and-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(oxetan-3-ylsulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-202).

Example 112-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-131)

To a solution of(R)-2-amino-6-fluoro-N-(4-(4-(pyrrolidin-3-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(synthesized according to a procedure similar to Example 2) wasdissolved in a mixture of DCE (5.0 mL) and AcOH (0.050 mL). Formaldehyde(37% in water, 47.46 mg, 0.5848 mmol) was added and the mixture wasstirred at RT for 30 mins. Triacetoxyboranuide (Sodium Ion (1)) (186 mg,0.8772 mmol) was added portionwise. The mixture was stirred at RT for 1hour and was quenched by the addition of water and methanol. The mixturewas concentrated under reduced pressure and the residue was purified byfractionlynx to yield2-amino-6-fluoro-N-(5-fluoro-4-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.MS (ES+) 455.2.

The following compounds were synthesized according to a proceduresimilar to Example 11:

-   (R)-2-amino-6-fluoro-N-(5-fluoro-4-(4-((1-methylpyrrolidin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-132);-   2-amino-6-fluoro-N-(4-(4-((1-methylpiperidin-4-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-154); and-   2-amino-6-fluoro-N-(4-(4-((1-methylazetidin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-N-164).

Example 122-amino-N-(5-cyano-4-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-113)

A mixture of2-amino-N-[5-bromo-4-(4-methylpiperazin-1-yl)-3-pyridyl]-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxamide(80.4 mg, 0.1790 mmol) synthesized according to a procedure similar toExample 1, Pd₂(dba)₃ (6.557 mg, 0.007160 mmol), zinc cyanide (18.92 mg,10.23 μL, 0.1611 mmol) and xantphos (8.286 mg, 0.01432 mmol) was placedin a sealed microwave tube and evacuated and flushed with nitrogen.Solvent DMF (1.6 mL) was added and nitrogen bubbled through the reaction(with needle as outlet and inlet) for 5 mins. The reaction was heated at120° C. for 1 h. LCMS shows reaction near completion, so cooled to roomtemperature and loaded onto an SCX-2 cartridge, eluting with MeOH andthen NH₃/MeOH. The basic fraction was evaporated and purified byfractionlynx and lyophilize to yield2-amino-N-(5-cyano-4-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. MS (ES+) 396.2.

Example 132-amino-N-(4-(4-(azetidine-3-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-194)

A solution of2-amino-N-[4-[4-(azetidine-3-carbonyl)piperazin-1-yl]-5-fluoro-3-pyridyl]-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxamide(Trifluoroacetic Acid (2)) (20 mg, 0.02918 mmol), (synthesized accordingto Example 9), and formaldehyde (3.552 μL of 37% w/v, 0.04377 mmol) inDMF (1 mL) was stirred for 1 h at RT. Triacetoxyboranuide (Sodium Ion(1)) (9.277 mg, 0.04377 mmol) was added and the reaction mixture wasstirred at RT for 2 hr before it was quenched by the addition ofmethanol. The crude mixture was purified by Fractionlynx HPLC. Theaqueous fractions were combined and lyophilised, yielding2-amino-N-(4-(4-(azetidine-3-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(3 mg, 21%). MS (ES+) 472.1.

Example 142-amino-N-(4-(4-(2-(azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-N-228)

1-(azetidin-1-yl)-2-chloro-ethanone (12.03 mg, 0.09003 mmol) was addedto a solution of2-amino-6-fluoro-N-(5-fluoro-4-piperazin-1-yl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Trifluoroacetic Acid (3)) (50 mg, 0.06002 mmol) (synthesized accordingto a procedure similar to Example 2) and Et₃N (30.37 mg, 41.83 μL,0.3001 mmol) in DMF (2 mL). The solution was stirred at RT for 18 hr.

The crude mixture was purified by Fractionlynx HPLC. The aqueousfractions were combined and lyophilised yielding2-amino-N-(4-(4-(2-(azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide(30 mg, 71%). MS (ES+) 472.1.

Compound Analytical Data Cmpd LCMS LCMS No. ES+ (Rt min) HNMR I-N-1413.3 0.58 ¹H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.46 (dd, J = 4.8,2.5 Hz, 1H), 9.42 (s, 1H), 8.82 (d, J = 2.5 Hz, 1H), 8.23 (d, J = 5.3Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 6.76 (s, 2H), 4.58 (t, J = 6.5 Hz,2H), 4.46 (t, J = 6.1 Hz, 2H), 3.60 (p, J = 6.3 Hz, 1H), 2.98 (t, J =4.7 Hz, 4H), 2.50 (t, J = 3.5 Hz, 4H). I-N-2 392.1 0.51 ¹H NMR (500 MHz,DMSO-d6) δ 9.94 (s, 1H), 9.47 (s, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.73(d, J = 2.1 Hz, 1H), 8.20 (d, J = 5.1 Hz, 1H), 7.18 (d, J = 5.3 Hz),6.77 (s, 3H), 4.14 (s, 2H), 3.14 (dt, J = 12.9, 3.5 Hz, 2H), 2.77 (dd, J= 9.8, 5.2 Hz, 1H), 2.72 (td, J = 11.8, 11.4, 2.8 Hz, 2H), 1.91-1.82 (m,2H), 1.67-1.55 (m, 2H). I-N-3 371.2 1.82* ¹H NMR (500 MHz, Methanol-d4)δ 2.43 (3H, s), 2.75-2.75 (4H, m), 3.1-3.13 (4H, m), 7.22-7.23 (1H, d),8.21-8.22 (1H, d), 8.72-8.73 (1H, d), 9.02-9.04 (1H, dd), 9.42 91H, s).I-N-4 399.2 2.16* — I-N-5 411.3 2.16* ¹H NMR (500 MHz, DMSO-d6) δ 9.82(s, 1H), 9.54 (s, 1H), 9.27 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 6.80(br, 2H), 3.23 (m, 4H), 2.93 (s, 3H), 2.52 (br, 4H), 2.13 (m, 1H), 1.09(m, 2H), 0.92 (m, 2H). I-N-6 460.2 0.67 ¹H NMR (500 MHz, Methanol-d4) δ9.64 (s, 2H), 9.00 (s, 1H), 8.23 (s, 1H), 3.82 (td, J = 11.5, 2.9 Hz,1H), 3.53-3.43 (m, 1H), 3.04-2.88 (m, 5H), 2.90-2.74 (m, 3H), 2.64-2.54(m, 1H), 2.42-2.36 (m, 1H), 2.35 (s, 3H), 2.02-1.92 (m, 1H). I-N-7 339.20.51 ¹H NMR (500 MHz, Methanol-d4) δ 9.62 (d, J = 0.6 Hz, 1H), 9.35 (t,J = 1.4 Hz, 1H), 9.03 (dd, J = 4.4, 2.5 Hz, 1H), 8.62 (d, J = 5.3 Hz,1H), 8.47 (dd, J = 2.6, 0.5 Hz, 1H), 7.98 (dd, J = 1.9, 1.5 Hz, 1H),7.86 (dd, J = 1.9, 1.3 Hz, 1H), 7.74 (dd, J = 5.2, 0.6 Hz, 1H). I-N-8396.3 0.55 ¹H NMR (500 MHz, Methanol-d4) δ 10.04 (d, J = 0.8 Hz, 1H),8.89 (dd, J = 4.4, 2.6 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.48 (dd, J =6.1, 0.8 Hz, 1H), 8.45 (d, J = 0.9 Hz, 1H), 8.06 (d, J = 0.7 Hz, 1H),8.02 (d, J = 6.3 Hz, 1H), 3.35 (dd, J = 8.3, 7.0 Hz, 2H), 3.05 (dd, J =8.0, 7.2 Hz, 2H), 2.78 (s, 3H). I-N-9 410.3 0.67 ¹H NMR (500 MHz,Methanol-d4) δ 10.06 (d, J = 0.9 Hz, 1H), 8.93-8.87 (m, 1H), 8.64 (dd, J= 2.6, 0.7 Hz, 1H), 8.49 (dd, J = 6.2, 0.8 Hz, 1H), 8.46 (d, J = 0.9 Hz,1H), 8.07 (s, 1H), 8.02 (d, J = 6.2 Hz, 1H), 3.51-3.44 (m, 2H),3.15-3.08 (m, 2H), 2.99 (s, 6H). I-N-10 427.3 0.59 ¹H NMR (500 MHz,Methanol-d4) δ 9.42 (s, 1H), 9.06-8.98 (m, 1H), 8.77-8.70 (m, 1H), 8.22(d, J = 5.4 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 5.4 Hz, 1H),5.53 (s, 2H), 4.00 (td, J = 8.6, 4.1 Hz, 1H), 3.94 (dd, J = 8.8, 6.8 Hz,1H), 3.83 (td, J = 8.5, 7.2 Hz, 1H), 3.73 (dd, J = 8.8, 6.5 Hz, 1H),3.22-3.15 (m, 1H), 3.15-3.06 (m, 4H), 2.90-2.80 (m, 2H), 2.78-2.69 (m,2H), 2.24-2.15 (m, 1H), 1.97-1.85 (m, 1H). I-N-11 ¹H NMR (500 MHz,Methanol-d4) δ 9.39 (d, J = 0.5 Hz, 1H), 9.05 (dd, J = 4.4, 2.6 Hz, 1H),8.74-8.68 (m, 1H), 8.23 (d, J = 5.5 Hz, 1H), 7.23 (dd, J = 5.5, 0.5 Hz,1H), 4.10-4.00 (m, 2H), 3.53-3.43 (m, 2H), 3.18-3.09 (m, 4H), 2.93-2.83(m, 4H), 2.60 (tt, J = 11.3, 3.8 Hz, 1H), 1.93 (dm, 2H), 1.60 (qd, J =12.2, 4.5 Hz, 2H). I-N-12 427.3 0.59 ¹H NMR (500 MHz, Methanol-d4) δ9.42 (s, 1H), 9.06-8.98 (m, 1H), 8.77-8.70 (m, 1H), 8.22 (d, J = 5.4 Hz,1H), 8.09 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 5.4 Hz, 1H), 5.53 (s, 2H),4.00 (td, J = 8.6, 4.1 Hz, 1H), 3.94 (dd, J = 8.8, 6.8 Hz, 1H), 3.83(td, J = 8.5, 7.2 Hz, 1H), 3.73 (dd, J = 8.8, 6.5 Hz, 1H), 3.22-3.15 (m,1H), 3.15-3.06 (m, 4H), 2.90-2.80 (m, 2H), 2.78-2.69 (m, 2H), 2.24-2.15(m, 1H), 1.97-1.85 (m, 1H). I-N-13 431.0 0.62 ¹H NMR (500 MHz, DMSO-d6)δ 10.26 (s, 1H), 9.49 (q, J = 2.3 Hz, 2H), 8.80 (d, J = 2.5 Hz, 1H),8.27 (d, J = 2.8 Hz, 1H), 6.79 (s, 2H), 4.60 (t, J = 6.5 Hz, 2H), 4.47(t, J = 6.0 Hz, 2H), 3.63 (p, J = 6.3 Hz, 1H), 3.13 (m, 4H), 2.50 (m,4H). I-N-14 405.1 0.7 ¹H NMR (500 MHz, DMSO-d6) δ 2.97 (3H, s), 3.21(2H, m), 3.41 (4H, m), 3.60 (masked signal), 6.86 (2H, br s), 8.32 (1H,d), 8.83 (1H, m), 9.47 (2H, m) and 10.00 (2H, m) ppm. I-N-15 389.0 0.65¹H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.50 (dd, J = 4.8, 2.5 Hz,1H), 9.49 (s, 1H), 8.77 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H),6.80 (s, 2H), 3.10 (t, J = 4.6 Hz, 4H), 2.59 (t, J = 4.8 Hz, 4H), 2.33(s, 3H). I-N-16 427.2 1.87* ¹H NMR (500 MHz, DMSO-d6) δ 10.1 (s, 1H),9.47 (s, 1H), 9.36 (s, 1H), 8.80, (s, 1H), 8.05 (s, 1H), 6.78 (br, 2H),4.59 (m, 2H), 4.45 (m, 2H), 3.57 (m, 1H), 3.12 (br, 4H) 2.52 (br, 4H),2.40 (s, 3H). I-N-17 385.2 1.99* ¹H NMR (500 MHz, DMSO-d6) δ1.26-1.28(3H, m), 3.20-3.40 (4H, masked), 3.60-3.80 (6H, m), 6.80 (2H, s),7.49-7.51 (1H, d), 8.44-8.45 (1H, d), 9.01-9.02 (1H, dd), 9.42 (1H, s),9.54-9.55 (1H, dd), 9.65 (1H, s), 9.90-10.05 (1H, br s). I-N-18 397.01.74* — I-N-19 ¹H NMR (500 MHz, Methanol-d4) δ 9.43 (d, J = 1.1 Hz, 1H),9.14 (dd, J = 4.3, 2.5 Hz, 1H), 8.84 (dd, J = 2.6, 0.6 Hz, 1H), 8.43(dd, J = 6.6, 1.1 Hz, 1H), 7.61 (d, J = 6.7 Hz, 1H), 4.23 (dd, J = 11.0,3.4 Hz, 1H), 4.11 (td, J = 8.7, 4.3 Hz, 1H), 4.04 (d, J = 6.2 Hz, 1H),3.92 (dd, J = 10.8, 6.1 Hz, 1H), 3.87-3.70 (m, 5H), 3.57-3.43 (m, 4H),2.52-2.39 (m, 1H), 2.24 (ddd, J = 10.5, 6.2, 2.9 Hz, 1H). I-N-20 439.22.52* — I-N-21 397.2 2.04* — I-N-22 415.4 0.62 ¹H NMR (500 MHz, DMSO-d6)δ 2.61 (2H, t), 2.68 (4H, m), 2.95 (4H, m), 3.26 (3H, s), 3.48 (2H, t),6.77 (2H, br s), 7.17 (1H, m), 8.22 (1H, d), 8.81 (1H, m), 9.42 (1H, s),9.48 (1H, dd) and 9.79 (1H, s) ppm. I-N-23 427.3 0.61 ¹H NMR (500 MHz,DMSO-d6) δ 10.33 (s, 1H), 9.65 (s, 1H), 9.47 (dd, J = 4.8, 2.5 Hz, 1H),8.79 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 5.2 Hz,1H), 6.76 (s, 2H), 4.61 (dt, J = 17.9, 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz,1H), 4.44 (t, J = 6.0 Hz, 1H), 3.61 (p, J = 6.3 Hz, 1H), 2.95 (d, J =11.1 Hz, 1H), 2.86-2.73 (m, 2H), 2.71-2.59 (m, 1H), 2.41-2.27 (m, 1H),2.12-2.02 (m, 1H), 0.83 (d, J = 6.2 Hz, 3H). 1H multiplet hidden underwater peak. I-N-24 427.3 0.64 ¹H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H),9.65 (s, 1H), 9.47 (dd, J = 4.8, 2.5 Hz, 1H), 8.79 (d, J = 2.5 Hz, 1H),8.27 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 6.76 (s, 2H), 4.61(dt, J = 17.9, 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 1H), 4.44 (t, J = 6.0Hz, 1H), 3.61 (p, J = 6.3 Hz, 1H), 2.95 (d, J = 11.2 Hz, 1H), 2.88-2.73(m, 2H), 2.71-2.58 (m, 1H), 2.41-2.26 (m, 1H), 2.06 (t, J = 9.8 Hz, 1H),0.82 (d, J = 6.1 Hz, 3H). 1H multiplet hidden under water peak. I-N-25443.0 0.68 ¹H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.49 (d, J = 2.2Hz, 1H), 9.21 (d, J = 1.1 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.46 (dd, J= 6.5, 1.0 Hz, 1H), 7.55 (d, J = 6.5 Hz, 1H), 6.82 (s, 2H), 4.69 (d, J =6.8 Hz, 2H), 4.31 (d, J = 6.9 Hz, 2H), 3.59 (s, 4H), 3.01 (s, 4H), 1.54(s, 3H). I-N-26 339.1 0.61 ¹H NMR (500 MHz, Acetone-d6) δ 11.17 (s, 2H),9.80 (t, J = 0.5 Hz, 1H), 8.99 (dd, J = 4.6, 2.6 Hz, 1H), 8.70 (d, J =2.6 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.30 (dd, J = 2.5, 0.6 Hz, 1H),8.05 (dd, J = 1.9, 0.6 Hz, 1H), 7.57 (dd, J = 5.3, 0.5 Hz, 1H), 6.65(dd, J = 2.5, 1.8 Hz, 1H), 6.37 (s, 1H). I-N-27 407.1 0.69 ¹H NMR (500MHz, Methanol-d4) δ 9.79 (s, 1H), 9.02 (dd, J = 4.4, 2.5 Hz, 1H), 8.52(d, J = 5.2 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.26 (dd, J = 1.2, 0.7Hz, 1H), 8.10 (t, J = 1.3 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H). I-N-28353.2 0.55 ¹H NMR (500 MHz, Methanol-d4) δ 9.66 (d, J = 0.6 Hz, 1H),9.08 (dd, J = 4.4, 2.5 Hz, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.49 (dd, J =2.5, 0.5 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H),7.72 (dd, J = 5.2, 0.6 Hz, 1H), 2.62 (s, 3H). I-N-29 355.1 0.56 ¹H NMR(500 MHz, Methanol-d4) δ 9.63 (d, J = 0.6 Hz, 1H), 9.14 (s, 1H), 9.03(d, J = 2.2 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H),7.90 (t, J = 1.7 Hz, 1H), 7.77 (t, J = 1.6 Hz, 1H), 7.71 (dd, J = 5.3,0.6 Hz, 1H). I-N-30 421.2 0.72 ¹H NMR (500 MHz, Methanol-d4) δ10.01-9.94 (m, 1H), 9.65 (s, 1H), 9.03 (dd, J = 4.4, 2.5 Hz, 1H), 8.52(d, J = 5.1 Hz, 1H), 8.27 (ddd, J = 2.6, 1.2, 0.5 Hz, 1H), 7.89 (q, J =1.4 Hz, 1H), 7.59 (dt, J = 5.1, 0.6 Hz, 1H), 2.32 (s, 3H). I-N-31 425.30.54 ¹H NMR (500 MHz, DMSO-d6) δ 9.45 (dd, J = 4.8, 2.6 Hz, 1H), 9.18(s, 1H), 8.80 (dd, J = 2.5, 0.5 Hz, 1H), 8.50 (s, 1H), 8.13 (d, J = 5.7Hz, 1H), 7.02 (d, J = 5.7 Hz, 1H), 6.65 (s, 2H), 4.60-4.50 (m, 4H), 3.70(p, J = 6.4 Hz, 1H), 3.42-3.27 (m, 1H), 3.17 (ddd, J = 12.6, 10.4, 2.7Hz, 1H), 2.76 (ddd, J = 8.1, 6.6, 4.2 Hz, 1H), 2.66 (ddd, J = 11.0, 4.1,2.5 Hz, 1H), 2.59-2.51 (m, 1H), 2.31-2.16 (m, 1H), 0.61 (td, J = 5.6,4.2 Hz, 1H), 0.37 (td, J = 6.8, 5.8 Hz, 1H). I-N-32 453.3 0.66 ¹H NMR(500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.48 (dd, J = 4.8, 2.5 Hz, 1H), 9.31(s, 1H), 8.81 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 0.6 Hz, 1H), 6.77 (s,2H), 4.59 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 3.66-3.51 (m,1H), 3.31-3.18 (m, 4H), 2.51 (p, J = 1.9 Hz, 4H), 2.13 (tt, J = 8.4, 5.4Hz, 1H), 1.11-1.01 (m, 2H), 0.90-0.78 (m, 2H). I-N-33 397.2 2.25* ¹H NMR(500 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.55 (d, J = 4.0 Hz, 1H), 9.38 (s,1H), 9.02 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H),6.80 (br, 2H), 2.90 (br, 8H), 0.87 (m, 2H), 0.80 (m, 2H). I-N-34 429.30.8 ¹H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H),9.37 (s, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.3 Hz, 1H), 7.16(dd, J = 5.3, 0.5 Hz, 1H), 6.81 (s, 2H), 2.93 (t, J = 4.6 Hz, 4H), 2.72(t, J = 4.7 Hz, 4H), 1.07 (s, 9H). I-N-35 431.2 0.6 ¹H NMR (500 MHz,DMSO-d6) δ 9.65 (s, 1H), 9.44 (d, J = 2.2 Hz, 1H), 9.29 (s, 1H), 8.58(d, J = 2.2 Hz, 1H), 8.21 (d, J = 5.3 Hz, 1H), 7.15 (dd, J = 5.3, 0.5Hz, 1H), 6.82 (s, 2H), 4.52-4.42 (m, 1H), 3.77 (t, J = 4.7 Hz, 1H),3.31-3.22 (m, 1H), 3.18 (d, J = 11.0 Hz, 1H), 2.76-2.60 (m, 1H),2.59-2.53 (m, 1H), 2.48-2.40 (m, 1H), 2.32 (s, 6H), 1.81-1.57 (m, 2H).I-N-36 445.2 0.7 ¹H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.53 (s,1H), 9.43 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.21 (d, J =5.2 Hz, 1H), 7.22 (dd, J = 5.3, 0.6 Hz, 1H), 6.81 (s, 2H), 4.24 (s, 1H),3.02 (td, J = 11.5, 10.3, 3.9 Hz, 2H), 2.87 (dd, J = 11.3, 4.2 Hz, 2H),2.33 (s, 6H), 2.31 (s, 2H), 2.07 (td, J = 12.5, 4.2 Hz, 2H), 1.50 (d, J= 12.8 Hz, 2H). I-N-37 415.2 0.7 — I-N-38 502.2 1.97* ¹H NMR (500 MHz,CDCl₃) δ 10.30 (s, 1H), 9.73 (s, 1H), 8.74 (s, 1H), 8.51 (dd, J = 3.8,2.5 Hz, 1H), 8.25 (s, 1H), 5.92 (s, 2H), 4.66 (dt, J = 19.3, 6.5 Hz,2H), 4.57 (s, 1H), 3.87 (s, 1H), 3.62-3.39 (m, 2H), 2.92 (s, 2H), 2.79(s, 2H), 2.65-2.44 (m, 2H), 2.28 (s, 1H), 1.89 (s, 1H), 1.67 (s, 2H).I-N-39 415.2 0.75 H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.43 (d, J =2.2 Hz, 1H), 9.37 (s, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.2Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.81 (s, 2H), 2.95 (t, J = 4.7 Hz,4H), 2.76 (s, 2H), 2.72-2.63 (m, 3H), 1.04 (d, J = 6.5 Hz, 6H). I-N-40415.2 0.72 ¹H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.44 (d, J = 2.2Hz, 1H), 9.34 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.3 Hz,1H), 7.18 (d, J = 5.3 Hz, 1H), 6.82 (s, 2H), 3.34-3.19 (m, 1H), 3.09 (d,J = 11.5 Hz, 1H), 2.69-2.47 (m, 3H), 2.09 (d, J = 5.2 Hz, 6H), 1.99 (d,J = 12.3 Hz, 1H), 1.90-1.70 (m, 2H), 1.28 (dd, J = 11.2, 6.4 Hz, 1H).I-N-41 421.1 0.75 ¹H NMR (500 MHz, DMSO-d6) δ 2.32 (3H, s), 2.60 (4H,m), 3.25 (4H, m), 6.85 (2H, br s), 8.26 (1H, s), 8.59 (1H, m), 9.44 (1H,m), 9.53 (1H, s) and 10.28 (1H, br s) ppm. I-N-42 414.1 0.65 ¹H NMR (500MHz, Methanol-d4) δ 9.05 (d, J = 2.2 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H),8.34 (d, J = 1.3 Hz, 1H), 8.09 (dd, J = 7.3, 1.4 Hz, 1H), 7.25 (d, J =7.3 Hz, 1H), 4.92 (d, J = 2.4 Hz, 2H), 4.05-4.01 (m, 1H), 2.45-2.37 (m,2H), 2.22-2.14 (m, 2H), 2.10-2.03 (m, 2H), 1.89-1.82 (m, 2H). I-N-43401.1 0.63 ¹H NMR (500 MHz, Methanol-d4) δ 8.89 (d, J = 2.2 Hz, 1H),8.62 (s, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 5.8 Hz, 1H), 6.96(d, J = 5.8 Hz, 1H), 3.45-3.39 (m, 2H), 3.39-3.31 (m, 2H), 2.72-2.67 (m,2H), 2.66-2.60 (m, 2H), 2.26 (s, 3H), 1.93-1.85 (m, 2H). I-N-44 410.10.6 ¹H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.54 (s, 1H), 9.36 (d, J= 2.2 Hz, 1H), 8.29 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H),7.33-7.21 (m, 2H), 6.93 (d, J = 1.3 Hz, 1H), 6.78 (s, 2H), 4.24-4.10 (m,4H), 3.62-3.50 (m, 2H). I-N-45 429.2 2.29* — I-N-46 459.2 0.8 ¹H NMR(500 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.50 (s, 1H), 9.43 (d, J = 2.2 Hz,1H), 8.69 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.21 (d, J =5.3 Hz, 1H), 6.81 (s, 2H), 3.16 (s, 3H), 2.94-2.83 (m, 4H), 2.40 (s,2H), 2.31 (s, 6H), 2.06-1.95 (m, 2H), 1.84-1.73 (m, 2H). I-N-47 431.20.66 ¹H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H),9.38 (s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.23 (d, J = 5.3 Hz, 1H), 7.17(dd, J = 5.4, 0.5 Hz, 1H), 6.82 (s, 2H), 3.50 (dd, J = 9.9, 4.1 Hz, 1H),3.28-3.23 (m, 1H), 3.18 (dd, J = 11.0, 2.3 Hz, 1H), 3.12 (s, 3H),3.07-3.00 (m, 1H), 2.89-2.77 (m, 2H), 2.61-2.53 (m, 1H), 2.50-2.45 (m,2H), 2.31 (s, 3H). I-N-48 427.2 0.79 ¹H NMR (500 MHz, DMSO-d6) δ 9.76(s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 9.40 (s, 1H), 8.58 (d, J = 2.2 Hz,1H), 8.22 (d, J = 5.3 Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.81 (s, 2H),2.94 (t, J = 4.8 Hz, 4H), 2.91-2.82 (m, 1H), 2.50-2.46 (m, 4H), 1.99(ddtd, J = 11.2, 8.7, 4.5, 2.6 Hz, 2H), 1.88-1.74 (m, 2H), 1.66 (tdd, J= 10.9, 6.0, 2.1 Hz, 2H). I-N-49 444.2 0.66 ¹H NMR (500 MHz, DMSO-d6) δ9.74 (s, 1H), 9.46-9.36 (m, 2H), 8.63 (d, J = 2.2 Hz, 1H), 8.22 (d, J =5.3 Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.81 (s, 2H), 2.94 (t, J = 4.7Hz, 4H), 2.69-2.62 (m, 4H), 2.53 (d, J = 6.9 Hz, 2H), 2.38 (dd, J = 7.8,5.8 Hz, 2H), 2.17 (s, 6H). I-N-50 402.1 0.61 ¹H NMR (500 MHz, DMSO-d6) δ9.39 (d, J = 2.2 Hz, 1H), 9.28 (s, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.60(s, 1H), 6.75 (s, 2H), 6.20 (s, 1H), 5.66 (s, 2H), 2.92-2.84 (m, 4H),2.50 (s, 4H), 2.24 (s, 3H). I-N-51 401.1 0.71 ¹H NMR (500 MHz, DMSO-d6)δ 9.75 (s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 9.40 (s, 1H), 8.62 (d, J = 2.3Hz, 1H), 8.23 (d, J = 5.3 Hz, 1H), 7.18 (d, J = 5.3 Hz, 1H), 6.81 (s,2H), 2.97 (t, J = 4.8 Hz, 4H), 2.64 (d, J = 9.5 Hz, 4H), 2.50-2.43 (m,2H), 1.05 (t, J = 7.1 Hz, 3H). I-N-52 421.0 0.75 ¹H NMR (500 MHz,DMSO-d6) δ 9.70 (s, 1H), 9.53 (s, 1H), 9.47 (d, J = 2.2 Hz, 1H), 9.25(s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 7.34 (s, 1H), 6.84 (s, 2H), 3.65-3.48(m, 4H), 3.32-3.21 (m, 2H), 3.15-3.04 (m, 2H), 2.97 (s, 3H). I-N-53415.2 0.71 ¹H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.44 (d, J = 2.2Hz, 1H), 9.31 (s, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.3 Hz,1H), 7.12 (dd, J = 5.4, 0.5 Hz, 1H), 6.84 (s, 2H), 2.88-2.81 (m, 2H),2.77 (s, 2H), 2.61 (t, J = 5.0 Hz, 2H), 2.19 (s, 3H), 1.14 (s, 6H).I-N-54 401.2 0.39 ¹H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.43 (d, J =2.2 Hz, 1H), 9.41 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.3Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.82 (s, 2H), 3.11-2.99 (m, 2H),2.90-2.75 (m, 2H), 2.60-2.52 (m, 1H), 2.49-2.42 (m, 1H), 2.43-2.34 (m,1H), 2.27 (s, 3H), 0.99 (d, J = 6.2 Hz, 3H). I-N-55 387.1 1.92* ¹H NMR(500 MHz, Methanol-d4) δ 9.27 (d, J = 0.9 Hz, 1H), 9.00 (d, J = 2.2 Hz,1H), 8.54 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 6.3, 0.9 Hz, 1H), 7.39 (d,J = 6.3 Hz, 1H), 3.74 (d, J = 11.8 Hz, 1H), 3.59-3.50 (m, 1H), 3.46 (d,J = 12.5 Hz, 1H), 3.38-3.22 (m, 2H), 3.13-3.02 (m, 1H), 2.95 (dd, J =11.9, 9.7 Hz, 1H), 2.20-2.06 (m, 2H), 1.95-1.80 (m, 3H), 1.57 (dtd, J =12.9, 10.5, 5.0 Hz, 2H). I-N-56 413.1 0.65 ¹H NMR (500 MHz, Methanol-d4)δ 9.10 (d, J = 2.2 Hz, 1H), 8.88 (d, J = 1.2 Hz, 1H), 8.67 (d, J = 2.2Hz, 1H), 8.36 (dd, J = 6.9, 1.2 Hz, 1H), 7.50 (d, J = 6.9 Hz, 1H), 4.59(ddd, J = 5.8, 3.8, 1.9 Hz, 1H), 4.14-4.04 (m, 2H), 3.74-3.67 (m, 2H),3.67-3.57 (m, 2H), 3.50 (ddd, J = 14.3, 11.3, 6.4 Hz, 2H), 2.51-2.41 (m,2H), 2.35-2.24 (m, 2H). I-N-57 401.2 0.68 ¹H NMR (500 MHz, DMSO-d6) δ2.30 (3H, s), 2.38 (3H, s), 2.57 (4H, m), 3.09 (4H, m), 6.83 (2H, br s),8.05 (1H, s), 8.60 (1H, m), 9.34 (1H, s), 9.43 (1H, s) and 10.12 (1H, brs) ppm I-N-58 429.1 0.62 ¹H NMR (500 MHz, Methanol-d4) δ 9.40 (d, J =0.5 Hz, 1H), 9.03 (d, J = 2.2 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.23(d, J = 5.5 Hz, 1H), 7.25 (dd, J = 5.5, 0.5 Hz, 1H), 4.76 (t, J = 6.7Hz, 2H), 4.65 (dd, J = 6.5, 5.9 Hz, 2H), 3.72-3.63 (m, 1H), 3.15 (t, J =4.9 Hz, 5H), 2.65 (t, J = 4.8 Hz, 5H). I-N-59 387.0 0.67 ¹H NMR (500MHz, DMSO-d6) δ 9.73 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H), 9.40 (s, 1H),8.64 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.3 Hz, 1H), 7.18 (dd, J = 5.3,0.5 Hz, 1H), 6.82 (s, 2H), 2.96 (t, J = 4.8 Hz, 4H), 2.56 (t, J = 4.5Hz, 4H), 2.28 (s, 3H). I-N-60 431.2 0.68 ¹H NMR (500 MHz, DMSO-d6) δ9.75 (s, 1H), 9.44-9.39 (m, 2H), 8.63 (d, J = 2.3 Hz, 1H), 8.22 (d, J =5.3 Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.81 (s, 2H), 3.49 (t, J = 5.6Hz, 2H), 3.26 (s, 3H), 2.95 (t, J = 4.7 Hz, 4H), 2.68 (d, J = 4.2 Hz,4H), 2.61 (t, J = 5.6 Hz, 2H). I-N-61 442.3 0.59 ¹H NMR (500 MHz,Methanol-d4) δ 9.39 (s, 1H), 9.13 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2Hz, 1H), 8.40 (dd, J = 6.7, 1.2 Hz, 1H), 7.60 (d, J = 6.7 Hz, 1H), 3.92(d, J = 12.7 Hz, 2H), 3.79 (d, J = 12.1 Hz, 2H), 3.60 (d, J = 12.3 Hz,2H), 3.10-2.97 (m, 2H), 2.95 (s, 3H), 2.86-2.58 (m, 5H). I-N-62 427.00.63 ¹H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.54 (dd, J = 4.8, 2.5Hz, 1H), 9.21 (d, J = 0.9 Hz, 1H), 8.80 (d, J = 2.5 Hz, 1H), 8.46 (dd, J= 6.5, 1.0 Hz, 1H), 7.54 (d, J = 6.5 Hz, 1H), 6.78 (s, 2H), 4.68 (d, J =7.0 Hz, 2H), 4.30 (d, J = 6.8 Hz, 2H), 3.58 (s, 4H), 2.98 (s, 4H), 1.54(s, 3H). I-N-63 417.1 0.47 ¹H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H),9.43 (d, J = 2.2 Hz, 1H), 9.40 (s, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.23(d, J = 5.3 Hz, 1H), 7.17 (dd, J = 5.3, 0.5 Hz, 1H), 6.81 (s, 2H), 4.43(t, J = 5.5 Hz, 1H), 3.63 (ddd, J = 11.0, 5.6, 3.9 Hz, 1H), 3.28-3.20(m, 1H), 3.08-2.97 (m, 1H), 2.93-2.75 (m, 2H), 2.54 (ddd, J = 11.1, 3.6,1.8 Hz, 2H), 2.37 (h, J = 1.7 Hz, 1H), 2.31 (s, 3H). I-N-64 413.2 0.77¹H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.41 (d, J = 2.2 Hz, 1H), 9.39(s, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.20 (d, J = 5.4 Hz, 1H), 7.14 (d, J= 5.4 Hz, 1H), 6.80 (s, 2H), 2.90 (t, J = 4.9 Hz, 4H), 2.77 (d, J = 5.3Hz, 4H), 1.80 (pd, J = 6.6, 4.2, 3.4 Hz, 1H), 0.45 (dq, J = 6.6, 4.3,3.8 Hz, 2H), 0.36-0.29 (m, 2H). I-N-65 413.1 1.61* ¹H NMR (500 MHz,DMSO-d6) δ 9.75 (s, 1H), 9.46-9.39 (m, 2H), 8.58 (d, J = 2.3 Hz, 1H),8.22 (d, J = 5.3 Hz, 1H), 7.20 (d, J = 5.4 Hz, 1H), 6.82 (s, 2H),3.26-3.20 (m, 1H), 3.14 (d, J = 11.5 Hz, 1H), 3.05-2.96 (m, 2H), 2.78(td, J = 11.4, 3.1 Hz, 1H), 2.63 (t, J = 10.3 Hz, 1H), 2.48-2.43 (m,1H), 2.33 (d, J = 7.7 Hz, 1H), 2.20 (q, J = 7.9 Hz, 1H), 1.79-1.66 (m,3H), 1.35 (tt, J = 14.8, 7.2 Hz, 1H). I-N-66 402.1 0.67 ¹H NMR (500 MHz,Methanol-d4) δ 9.42 (d, J = 0.5 Hz, 1H), 9.04 (d, J = 2.2 Hz, 1H), 8.62(d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.4 Hz, 1H), 7.27 (dd, J = 5.5, 0.5Hz, 1H), 3.24-3.14 (m, 2H), 3.06 (dd, J = 11.1, 5.6 Hz, 2H), 1.94 (ddd,J = 13.6, 9.8, 4.0 Hz, 2H), 1.85 (d, J = 13.2 Hz, 2H), 1.37 (s, 3H).I-N-67 455.1 0.84 ¹H NMR (500 MHz, DMSO-d6) δ 2.89 (4H, m), 2.97 (4H,m), 3.37 masked signal, 6.82 (2H, br s), 7.20 (1H, m), 8.22 (1H, m),8.70 (1H, m), 9.43 (2H, m) and 9.75 (1H, s) ppm. I-N-68 406.2 0.53 ¹HNMR (500 MHz, Methanol-d4) δ 9.45 (d, J = 1.1 Hz, 1H), 9.11 (d, J = 2.2Hz, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.41 (dd, J = 6.6, 1.1 Hz, 1H), 7.68(d, J = 6.6 Hz, 1H), 4.02 (ddd, J = 13.6, 11.1, 2.0 Hz, 2H), 3.83-3.75(m, 2H), 3.33-3.28 (m, 2H), 3.16-3.08 (m, 2H). I-N-69 430.2 0.75 ¹H NMR(500 MHz, Methanol-d4) δ 9.23 (d, J = 1.3 Hz, 1H), 9.10 (d, J = 2.2 Hz,1H), 8.68 (d, J = 2.2 Hz, 1H), 8.30 (dd, J = 6.8, 1.3 Hz, 1H), 7.52 (d,J = 6.8 Hz, 1H), 4.00 (dt, J = 13.0, 2.8 Hz, 2H), 3.15-3.03 (m, 2H),2.00-1.90 (m, 2H), 1.74 (qd, J = 12.6, 3.8 Hz, 2H), 1.66-1.60 (m, 1H),1.25 (s, 6H). I-N-70 441.1 0.71 ¹H NMR (500 MHz, DMSO-d6) δ 9.77 (s,1H), 9.50-9.40 (m, 2H), 8.77 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 5.3 Hz,1H), 7.25 (dd, J = 5.3, 0.5 Hz, 1H), 6.82 (s, 2H), 3.84-3.65 (m, 1H),3.22 (d, J = 11.0 Hz, 1H), 3.12-2.90 (m, 3H), 2.81 (dd, J = 10.9, 10.1Hz, 1H), 2.76-2.59 (m, 1H). I-N-71 413.1 0.72 ¹H NMR (500 MHz, DMSO-d6)δ 9.75 (s, 1H), 9.44-9.38 (m, 2H), 8.58 (d, J = 2.2 Hz, 1H), 8.22 (d, J= 5.3 Hz, 1H), 7.20 (dd, J = 5.4, 0.5 Hz, 1H), 6.82 (s, 2H), 3.31-3.20(m, 2H), 3.14 (dd, J = 10.8, 2.9 Hz, 1H), 3.07-2.96 (m, 2H), 2.78 (td, J= 11.4, 2.9 Hz, 1H), 2.66-2.60 (m, 1H), 2.34 (s, 1H), 2.19 (q, J = 8.4Hz, 1H), 1.73 (tdd, J = 13.4, 7.9, 4.2 Hz, 3H), 1.35 (td, J = 10.5, 5.8Hz, 1H). I-N-72 401.2 0.69 ¹H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H),9.62 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.26(d, J = 5.1 Hz, 1H), 7.34 (d, J = 5.2 Hz, 1H), 6.82 (s, 2H), 3.00-2.89(m, 1H), 2.90-2.81 (m, 1H), 2.81-2.73 (m, 1H), 2.72-2.62 (m, 1H),2.47-2.39 (m, 1H), 2.30 (s, 3H), 2.24-2.11 (m, 1H), 0.82 (d, J = 6.2 Hz,3H). (One proton hidden under DMSO peak). I-N-73 402.1 0.76 ¹H NMR (500MHz, DMSO-d6) δ 9.83 (s, 1H), 9.50-9.35 (m, 2H), 8.58 (d, J = 2.2 Hz,1H), 8.21 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 5.3 Hz, 1H), 6.82 (s, 2H),3.44 (dt, J = 7.9, 4.0 Hz, 1H), 3.30 (s, 3H), 3.12-3.03 (m, 2H), 2.79(ddd, J = 11.8, 8.8, 3.1 Hz, 2H), 2.07-1.98 (m, 2H), 1.75 (dtd, J =12.2, 8.5, 3.4 Hz, 2H). I-N-74 430.2 0.8 ¹H NMR (500 MHz, Methanol-d4) δ9.44 (d, J = 1.2 Hz, 1H), 9.10 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz,1H), 8.34 (dd, J = 6.7, 1.2 Hz, 1H), 7.56 (d, J = 6.7 Hz, 1H), 3.84-3.79(m, 2H), 3.78 (s, 3H), 3.23-3.14 (m, 2H), 2.80-2.72 (m, 1H), 2.22-2.06(m, 4H). I-N-75 410.1 0.57 ¹H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H),9.54 (s, 1H), 9.36 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.72(d, J = 1.0 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 5.3, 0.5Hz, 1H), 6.78 (s, 2H), 6.66 (d, J = 1.0 Hz, 1H), 4.34-4.11 (m, 4H),3.59-3.44 (m, 2H). I-N-76 420.2 0.67 ¹H NMR (500 MHz, DMSO-d6) δ 1.85(6H, s), 2.95 (3H, s), 3.2-3.4 (4H, m), 3.6-3.8 (4H, m), 6.8 (1H, brs),7.47 (1H, d), 8.47 (1H, d), 9.05 (1H, s), 9.15 (1H, s), 9.45 (1H, s),9.75 (1H, s), 10.0 (1H, brs). I-N-77 363.1 1.89* — I-N-78 406.2 0.62 ¹HNMR (500 MHz, DMSO-d6) δ 1.7 (3H, d), 2.95 (3H, s), 3.2-3.4 (4H, m),3.6-3.8 (4H, m), 4.5 (1H, q), 6.8 (1H, brs), 7.49 (1H, d), 8.47 (1H, d),8.95 (1H, s), 9.18 (1H, s), 9.40 (1H, s), 9.75 (1H, s), 10.1 (1H, brs).I-N-79 391.2 2.32* — I-N-80 410.1 0.65 ¹H NMR (500 MHz, DMSO-d6) δ 2.99(3H, br s), 3.18 (2H, m), 3.37-3.44 (4H, m), 3.67 (2H, m), 4.15 (2H, s),6.80 (2H, br s), 8.32 (1H, d), 8.76 (1H, d), 9.12 (1H, d), 9.51 (1H, s),9.86 (1H, br s) and 10.19 (1H, s) ppm. I-N-81 379.2 1.79* ¹H NMR (500MHz, DMSO-d6) δ 9.79 (s, 1H), 9.36 (s, 1H), 9.10 (d, J = 2.0 Hz, 1H),8.77 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 6.4 Hz, 1H), 7.49 (d, J = 6.4 Hz,1H), 6.78 (s, 2H), 4.15 (s, 2H), 3.87-3.83 (m, 4H), 3.33-3.29 (m, 4H).I-N-82 92.2 1.74* ¹H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.42 (s,1H), 9.12 (d, J = 1.9 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.45 (d, J =6.2 Hz, 1H), 7.52 (d, J = 6.2 Hz, 1H), 6.80 (s, 2H), 4.15 (s, 2H),3.90-3.68 (m, 4H), 3.68-3.55 (m, 3H), 2.96 (s, 3H). I-N-83 393.2 0.53 ¹HNMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.46 (s, 1H), 9.06 (dt, J = 2.0,0.8 Hz, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 5.3 Hz, 1H),7.21-7.16 (m, 1H), 6.77 (s, 2H), 4.73 (d, J = 4.3 Hz, 1H), 4.14 (d, J =0.7 Hz, 2H), 3.71 (s, 1H), 3.12 (d, J = 11.5 Hz, 2H), 2.77 (t, J = 9.6Hz, 2H), 1.92 (s, 2H), 1.73 (t, J = 9.2 Hz, 2H). I-N-84 377.2 2.38* —I-N-85 405.2 0.69 ¹H NMR (500 MHz, Methanol-d4) δ 9.56 (s, 1H), 9.07(dd, J = 4.3, 2.6 Hz, 1H), 8.82-8.77 (m, 1H), 8.25 (s, 1H), 3.38-3.36(m, 4H), 2.84 (d, J = 4.4 Hz, 4H), 2.50 (s, 3H). I-N-86 387.1 0.56 ¹HNMR (500 MHz, Methanol-d4) δ 9.30 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H),8.69 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.10 (d, J = 5.5 Hz,1H), 2.81 (td, J = 10.9, 5.5 Hz, 1H), 2.71 (td, J = 12.0, 2.4 Hz, 2H),1.87 (d, J = 12.4 Hz, 2H), 1.66 (qd, J = 12.1, 3.8 Hz, 2H), 3.26-3.23(m, 2H). I-N-87 401.1 1.85* — I-N-88 373.0 1.16* ¹H NMR (500 MHz,DMSO-d6) δ 9.82 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H), 9.41 (s, 1H), 8.67(d, J = 2.2 Hz, 1H), 8.23 (d, J = 5.3 Hz, 1H), 7.16 (d, J = 5.3 Hz, 1H),6.82 (s, 2H), 2.93 (dd, J = 6.2, 3.3 Hz, 4H), 2.85 (dd, J = 6.1, 3.2 Hz,4H). I-N-89 378.1 0.97 ¹H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.44(s, 1H), 9.06 (d, J = 1.9 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.22 (d, J= 5.2 Hz, 1H), 7.16 (d, J = 5.3 Hz, 1H), 6.77 (s, 2H), 4.15 (s, 2H),2.95 (d, J = 4.7 Hz, 4H), 2.88-2.85 (m, 4H). I-N-90 408.2 0.51 ¹H NMR(500 MHz, DMSO-d6) δ 9.90 (d, J = 14.9 Hz, 1H), 9.51 (d, J = 4.6 Hz,1H), 9.04 (dd, J = 22.0, 2.2 Hz, 1H), 8.67 (dd, J = 24.9, 2.2 Hz, 1H),8.24 (d, J = 5.3 Hz, 1H), 7.19 (dd, J = 13.7, 5.3 Hz, 1H), 6.76 (d, J =10.4 Hz, 2H), 4.14 (d, J = 7.0 Hz, 2H), 3.99-3.79 (m, 2H), 3.77-3.68 (m,1H), 3.20 (d, J = 11.4 Hz, 1H), 3.16-3.00 (m, 1H), 2.90-2.73 (m, 1H),2.71-2.53 (m, 3H). I-N-91 401.1 0.6 ¹H NMR (500 MHz, DMSO-d6) δ 1.47(2H, m), 1.82 (3H, m), 2.85 (2H, m), 2.96 (2H, m), 3.66 (2H, m), 6.83(2H, br s), 7.46 (1H, d), 7.90 (3H, br s), 8.40 (1H, m), 8.76 (1H, s),9.27 (1H, s), 9.47 (1H, m) and 9.57 (1H, s) ppm. I-N-92 ¹H NMR (500 MHz,DMSO-d6) δ 12.39 (s, 1H), 9.81 (s, 1H), 9.45 (d, J = 2.2 Hz, 1H), 9.41(s, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 5.5 Hz, 1H), 3.45-3.40(m, 2H), 7.40 (d, J = 6.1 Hz, 1H), 6.83 (s, 2H), 3.04-2.86 (m, 2H),2.60-2.55 (m, 1H), 2.05-1.85 (m, 4H). I-N-93 427.2 2.2* — I-N-94 470.22.15* — I-N-95 471.2 2.27* — I-N-96 469.3 0.66 ¹H NMR (500 MHz, DMSO-d6)δ 9.86 (s, 1H), 9.52-9.31 (m, 2H), 8.62 (d, J = 2.2 Hz, 1H), 8.21 (d, J= 5.3 Hz, 1H), 7.17 (dd, J = 5.3, 0.5 Hz, 1H), 6.81 (s, 2H), 4.63 (s,4H), 3.27 (s, 4H), 3.13-3.02 (m, 2H), 2.76-2.66 (m, 2H), 2.14 (dq, J =8.3, 4.4, 3.8 Hz, 1H), 1.84-1.70 (m, 2H), 1.57-1.41 (m, 2H). I-N-97470.3 0.64 ¹H NMR (500 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.49 (d, J = 2.2Hz, 1H), 9.14 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 6.5, 1.1Hz, 1H), 7.46 (d, J = 6.6 Hz, 1H), 6.82 (s, 2H), 3.77 (d, J = 12.8 Hz,2H), 3.25-3.11 (m, 3H), 3.11-3.00 (m, 3H), 3.00-2.89 (m, 2H), 2.77 (s,3H), 2.58-2.53 (m, 2H), 2.49-2.45 (m, 1H), 1.99-1.85 (m, 2H), 1.77-1.59(m, 2H). I-N-98 459.2 2.43* — I-N-99 483.3 0.69 ¹H NMR (500 MHz,DMSO-d6) δ 10.43 (s, 1H), 9.53-9.46 (m, 2H), 9.34-9.23 (m, 1H), 8.83 (d,J = 2.2 Hz, 1H), 8.43 (dd, J = 6.5, 1.0 Hz, 1H), 7.50 (d, J = 6.5 Hz,1H), 6.84 (s, 2H), 4.70-4.42 (m, 3H), 4.04-3.90 (m, 2H), 3.89-3.74 (m,3H), 3.24-3.09 (m, 1H), 3.10-2.90 (m, 2H), 2.46-2.39 (m, 1H), 2.33-2.12(m, 3H), 2.00-1.73 (m, 2H). 2 proton signals hidden by water. I-N-100489.2 0.61 ¹H NMR (500 MHz, Methanol-d4) δ 9.35 (s, 1H), 9.06 (d, J =2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 5.4 Hz, 1H),7.27-7.20 (m, 1H), 3.12-3.00 (m, 2H), 3.00-2.90 (m, 2H), 2.90-2.79 (m,2H), 2.74-2.63 (m, 2H), 2.11-2.04 (m, 1H), 2.04-1.86 (m, 4H), 1.36 (d, J= 19.8 Hz, 4H). I-N-101 493.2 1.4* ¹H NMR (500 MHz, Methanol-d4) δ 9.18(d, J = 1.3 Hz, 1H), 9.08 (d, J = 2.2 Hz, 1H), 8.86 (d, J = 1.3 Hz, 1H),8.69 (d, J = 2.2 Hz, 1H), 8.32 (dd, J = 6.8, 1.4 Hz, 1H), 7.54 (d, J =6.9 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 4.44-4.35 (m, 2H), 4.10-3.98 (m,4H), 3.29-3.17 (m, 4H), 3.03-2.92 (m, 1H), 2.19-2.10 (m, 2H), 1.99-1.88(m, 2H), 1.39-1.26 (m, 1H), 0.92 (d, J = 7.0 Hz, 1H). I-N-102 493.2 1.4*¹H NMR (500 MHz, Methanol-d4) δ 9.16 (d, J = 1.3 Hz, 1H), 9.12 (d, J =2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.32 (dd, J = 6.9, 1.3 Hz, 1H),7.56 (q, J = 2.1 Hz, 2H), 7.54 (d, J = 6.9 Hz, 1H), 4.28 (t, J = 5.3 Hz,2H), 4.06 (dm, J = 13.0 Hz, 2H), 3.33-3.19 (m, 4H), 2.99-2.93 (m, 1H),2.14 (d, J = 12.4 Hz, 2H), 1.98-1.87 (m, 2H), 1.39-1.29 (m, 3H),0.95-0.89 (m, 1H). I-N-103 459.2 2.42* — I-N-104 457.3 0.67 ¹H NMR (500MHz, DMSO-d6) δ 10.25 (s, 1H), 9.55 (s, 1H), 9.49 (d, J = 2.2 Hz, 1H),9.23 (d, J = 0.9 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.43 (dd, J = 6.4,1.0 Hz, 1H), 7.49 (d, J = 6.5 Hz, 1H), 6.83 (s, 2H), 4.20-3.93 (m, 2H),3.91-3.79 (m, 2H), 3.30-3.09 (m, 1H), 3.03 (t, J = 12.1 Hz, 2H),2.27-2.13 (m, 2H), 1.86 (qd, J = 12.5, 3.7 Hz, 2H). Remaining signalsfor 6 protons under water peak. I-N-105 441.0 2.26* — I-N-106 484.32.29* — I-N-107 457.2 2.24* — I-N-108 463.2 2.55* — I-N-109 469.3 0.69¹H NMR (500 MHz, DMSO-d6) δ 9.54-9.45 (m, 2H), 9.31 (d, J = 1.1 Hz, 1H),8.82 (d, J = 2.2 Hz, 1H), 8.43 (dd, J = 6.4, 1.0 Hz, 1H), 7.49 (d, J =6.5 Hz, 1H), 6.94-6.73 (m, 2H), 5.51-4.98 (m, 1H), 4.85 (d, J = 9.2 Hz,2H), 4.83-4.51 (m, 1H), 3.93-3.66 (m, 6H), 3.09 (t, J = 12.3 Hz, 2H),2.76-2.54 (m, 1H), 2.32-1.57 (m, 4H). (Aliphatic signals broad andundefined). I-N-110 447.2 0.67 ¹H NMR (500 MHz, DMSO-d6) δ 10.31 (s,1H), 9.56 (s, 1H), 9.50 (dd, J = 4.8, 2.5 Hz, 1H), 8.80 (d, J = 2.5 Hz,1H), 8.27 (s, 1H), 6.80 (s, 2H), 4.61 (t, J = 6.4 Hz, 2H), 4.47 (t, J =6.0 Hz, 2H), 3.70-3.51 (m, 1H), 3.44-3.20 (m, 4H), 2.60-2.45 (m, 4H).I-N-111 421.2 2.1* ¹H NMR (500 MHz, DMSO-d6) δ 9.73 (1H, br), 9.68 (1H,s), 9.54 (1H, d, J = 5.0 Hz), 8.95 (1 H, d, J = 5.0 Hz), 8.55 (1 H, s),7.37 (1H, t, J = 55 Hz), 6.79 (2H, br), 2.88 (3H, s) 3.47-3.22 (8 H,br). I-N-112 425.3 1.67* ¹H NMR (500 MHz, DMSO-d6) δ 9.45 (dd, J = 4.8,2.6 Hz, 1H), 9.18 (s, 1H), 8.80 (dd, J = 2.5, 0.5 Hz, 1H), 8.50 (s, 1H),8.13 (d, J = 5.7 Hz, 1H), 7.02 (d, J = 5.7 Hz, 1H), 6.65 (s, 2H),4.60-4.50 (m, 4H), 3.70 (p, J = 6.4 Hz, 1H), 3.42-3.27 (m, 1H), 3.17(ddd, J = 12.6, 10.4, 2.7 Hz, 1H), 2.76 (ddd, J = 8.1, 6.6, 4.2 Hz, 1H),2.66 (ddd, J = 11.0, 4.1, 2.5 Hz, 1H), 2.59-2.51 (m, 1H), 2.31-2.16 (m,1H), 0.61 (td, J = 5.6, 4.2 Hz, 1H), 0.37 (td, J = 6.8, 5.8 Hz, 1H).I-N-113 396.2 1.93* ¹H NMR (500 MHz, DMSO-d6) δ 9.82 (1H, br), 9.71 (1H, d, J = 2.2 Hz), 9.54 (1H, dd, J = 5.0, 2.2 Hz), 9.46 (1 H, s), 8.98(1H, s), 8.66 (1 H, s), 6.77 (2 H, br), 3.63-3.41 (6 H, br), 3.17 (2 H,br), 2.92 (3 H, s). I-N-114 444.3 1.96* ¹H NMR (500 MHz, methanol-d4) δ10.41 (s, 1H), 9.57 (d, J = 1.6 Hz, 1H), 9.08 (dd, J = 4.4, 2.4 Hz, 1H),8.87 (d, J = 2.5 Hz, 1H), 8.20 (d, J = 3.0 Hz, 1H), 3.53-3.44 (m, 1H),3.43-3.39 (m, 1H), 3.26-3.18 (m, 1H), 3.18-3.06 (m, 3H), 3.02 (dt, J =11.3, 2.5 Hz, 1H), 2.99-2.92 (m, 1H), 2.92-2.85 (m, 1H), 2.85-2.78 (m,1H), 2.74 (s, 3H), 2.71-2.66 (m, 1H), 2.63 (d, J = 17.2 Hz, 1H). I-N-115413.2 1.82* ¹H NMR (500 MHz, methanol-d4) δ 9.49 (s, 1H), 9.06 (d, J =4.5 Hz, 1H), 8.77 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 7.24 (d, J = 5.7Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 3.83-3.62 (m, 2H), 3.46-3.25 (m,2H), 3.24-3.00 (m, 2H), 2.94 (d, J = 11.2 Hz, 1H), 2.83 (d, J = 11.6 Hz,1H), 2.80-2.66 (m, 2H), 2.65-2.48 (m, 2H). I-N-116 413.2 1.82* ¹H NMR(500 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.48 (dd, J = 4.8, 2.5 Hz, 1H), 9.45(s, 1H), 8.83-8.78 (m, 1H), 8.21 (d, J = 5.3 Hz, 1H), 7.17 (dd, J = 5.3,0.5 Hz, 1H), 6.77 (s, 2H), 3.79 (dm, J = 10.9 Hz, 1H), 3.59 (dd, J =10.8, 2.8 Hz, 1H), 3.53 (td, 1H), 3.16-3.08 (m, 2H), 2.97 (dm, 1H), 2.86(td, 1H), 2.78 (dm, J = 11.1 Hz, 1H), 2.68 (dm, J = 11.5 Hz, 1H), 2.63(p, J = 1.8 Hz, 1H), 2.59-2.53 (m, 1H), 2.40 (dd, J = 11.5, 3.3 Hz, 1H),2.36 (p, J = 1.9 Hz, 1H). I-N-117 447.1 2.10* ¹H NMR (500 MHz, DMSO-d6)δ 10.22 (s, 1H), 2.54-2.51 (m, 2H), 9.47 (s, 1H), 9.43 (d, J = 2.2 Hz,1H), 8.60 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 6.83 (s, 2H),4.60 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 4.08 (q, J = 5.3 Hz,2H), 3.62-3.54 (m, 1H), 3.15-3.08 (m, 4H). I-N-118 375.1 1.84* ¹H NMR(500 MHz, DMSO-d6) δ 3.34 (m, 8H), 6.83 (2H, br s), 8.32 (1H, m), 8.74(2H, br s), 8.94 (1H, m), 9.55 (1H, m), 9.61 (1H, s) and 10.32 (1H, s)ppm. I-N-119 467.3 2.18* ¹H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.48(dd, J = 4.8, 2.5 Hz, 1H), 9.28 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 7.96(d, J = 0.6 Hz, 1H), 6.78 (s, 2H), 3.91-3.76 (m, 2H), 3.75-3.65 (m, 1H),3.48 (t, J = 7.7 Hz, 1H), 3.32-3.12 (m, 4H), 3.09-2.92 (m, 1H),2.80-2.66 (m, 2H), 2.65-2.54 (m, 2H), 2.19-1.97 (m, 2H), 1.84-1.63 (m,1H), 1.09-0.97 (m, 2H), 0.90-0.77 (m, 2H). I-N-120 467.3 2.18* ¹H NMR(500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.48 (dd, J = 4.8, 2.5 Hz, 1H), 9.28(s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 0.6 Hz, 1H), 6.77 (s,2H), 3.90-3.76 (m, 2H), 3.76-3.63 (m, 1H), 3.55-3.42 (m, 1H), 3.31-3.12(m, 4H), 2.99 (t, J = 7.2 Hz, 1H), 2.77-2.66 (m, 2H), 2.63-2.54 (m, 2H),2.17-1.95 (m, 2H), 1.79-1.64 (m, 1H), 1.08-0.99 (m, 2H), 0.89-0.78 (m,2H). I-N-121 459.2 2.13* ¹H NMR (500 MHz, DMSO-d6) δ 1.65-1.73 (2H, m),2.09 (2H, m), 3.16 (2H, m), 3.38 (5H, m), 3.49 (3H, m), 3.72 (1H, m),4.02 (2H, m), 6.80 (2H, br s), 8.33 (1H, d), 8.96 (1H, d), 9.46 (1H, s),9.54 (1H, m), 9.78 (1H, br s) and 10.09 (1H, s) ppm. I-N-122 445.2 1.99*¹H NMR (500 MHz, DMSO-d6) δ 2.12-2.17 (1H, m), 2.35-2.42 (1H, m),3.22-3.47 (6H, m), 3.73 masked signal, 3.95-4.09 (5H, m), 6.81 (2H, brs), 8.33 (1H, d), 8.97 (1H, m), 9.50 (1H, s), 9.54 (1H, d) and 10.09(2H, m) ppm. I-N-123 455.3 1.97* ¹H NMR (500 MHz, DMSO-d6) δ 10.05 (1 H,br), 9.48 (1 H, d, J = 5.2 Hz), 9.24 (1 H, m), 8.79 (1 H, br), 8.06 (1H, d, J = 5.2 Hz), 6.77 (2 H, br), 3.92 (2 H, br), 3.35-3.32 (7 H, br),2.70 (4 H, br), 2.39 (3 H, s), 1.78 (2 H, br), 1.55 (2 H, br). I-N-124461.2 2.11* ¹H NMR (500 MHz, DMSO-d6) δ 2.1-2.12 (1H, m), 2.4-2.5 (1H,m), 3.2-3.4 (4H, m), 3.6-3.85 (5H, m), 3.9-4.1 (4H, m), 6.78 (2H, brs),8.35 (1H, s), 8.92 (1H, s), 9.5-9.6 (2H, m), 10.0-10.15 (2H, m). I-N-125445.2 1.99* ¹H NMR (500 MHz, DMSO-d6) δ 2.12-2.17 (1H, m), 2.35-2.42(1H, m), 3.22-3.47 (6H, m), 3.73 masked signal, 3.95-4.09 (5H, m), 6.81(2H, br s), 8.32 (1H, d), 8.98 (1H, m), 9.50 (1H, s), 9.54 (1H, d) and10.09 (2H, m) ppm. I-N-126 391.1 1.97* ¹H NMR (500 MHz, DMSO-d6) δ 10.35(s, 1H), 9.72 (s, 1H), 9.55 (dd, J = 4.7, 2.5 Hz, 1H), 8.93 (dd, J =2.5, 0.7 Hz, 1H), 8.85 (s, 2H), 8.32 (s, 1H), 6.85 (s, 2H), 3.43-3.27(m, 4H), 2.58-2.45 (m, 4H). I-N-127 433.2 2.11* ¹H NMR (500 MHz,DMSO-d6) δ 2.64 (2H, t), 2.70 (4H, m), 3.09 (4H, m), 3.27 (3H, s), 3.51(2H, t, J = 5 Hz), 6.80 (2H, br s), 8.25 (1H, d), 8.77 (1H, m), 9.50(2H, m) and 10.30 (1H, s) ppm. I-N-128 500.1 2.13* ¹H NMR (500 MHz,methanol-d4) δ 9.54 (bs, 1H), 9.07 (dd, J = 4.3, 2.5 Hz, 1H), 8.71 (d, J= 2.5 Hz, 1H), 8.34 (bs, 1H), 4.02-3.85 (m, 4H), 3.62 (dm, J = 12.6 Hz,2H), 3.50-3.42 (m, 1H), 3.41-3.35 (m, 2H), 3.32-3.21 (m, 2H), 3.17-3.03(m, 2H), 2.91 (s, 3H), 2.05 (2m, 4H). I-N-129 400.2 1.88* ¹H NMR (500MHz, DMSO-d6) δ 10.36 (s, 1H), 9.52 (dd, J = 4.8, 2.5 Hz, 1H), 9.32 (s,1H), 9.05 (dd, J = 2.6, 0.6 Hz, 1H), 8.66 (s, 1H), 8.21 (s, 1H), 6.75(s, 2H), 6.55 (s, 1H), 3.86-3.03 (m, 8H, under water peak), 2.95 (s,3H), 2.94 (s, 3H). I-N-130 512.2 2.18* ¹H NMR (500 MHz, methanol-d4) δ10.26 (s, 1H), 9.50 (s, 1H), 9.03 (dd, J = 4.3, 2.5 Hz, 1H), 8.68 (dd, J= 2.5, 0.5 Hz, 1H), 8.35 (d, J = 4.1 Hz, 1H), 4.03-3.82 (m, 5H),3.58-3.51 (m, 1H), 3.49-3.37 (m, 5H), 3.30-3.27 (m, 3H), 2.35 (d, J =3.1 Hz, 1H), 2.18-2.09 (m, 1H), 2.09-2.01 (m, 2H), 2.01-1.87 (m, 2H).I-N-131 455.2 2.23* ¹H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.49 (dd,J = 4.8, 2.5 Hz, 1H), 9.43 (s, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.21 (d, J= 5.3 Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.77 (s, 2H), 4.18 (ddt, J =7.6, 6.3, 3.7 Hz, 1H), 3.56 (tt, J = 7.9, 3.8 Hz, 1H), 3.13-3.01 (m,2H), 2.79 (ddt, J = 12.2, 8.4, 3.1 Hz, 2H), 2.67 (dd, J = 9.7, 6.3 Hz,1H), 2.54-2.51 (m, 1H), 2.44-2.31 (m, 2H), 2.23 (s, 3H), 2.13-1.94 (m,3H), 1.83-1.70 (m, 2H), 1.70-1.61 (m, 1H). I-N-132 473.2 2.52* ¹H NMR(500 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.55 (s, 1H), 9.54-9.46 (m, 1H),8.70 (d, J = 2.5 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 6.80 (s, 2H), 4.23(ddt, J = 7.4, 6.3, 3.6 Hz, 1H), 3.64 (dt, J = 8.8, 4.5 Hz, 1H),3.19-3.08 (m, 2H), 3.07-2.97 (m, 2H), 2.72 (dd, J = 9.7, 6.2 Hz, 1H),2.60-2.53 (m, 1H), 2.47-2.34 (m, 2H), 2.26 (s, 3H), 2.15-1.98 (m, 3H),1.91-1.79 (m, 2H), 1.75-1.64 (m, 1H). I-N-133 441.2 1.78* ¹H NMR (500MHz, DMSO-d6) δ 10.35 (s, 2H), 9.55 (dd, J = 4.7, 2.5 Hz, 1H), 9.50 (s,1H), 9.44 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 6.0 Hz, 1H),7.59 (d, J = 6.0 Hz, 1H), 4.00-3.81 (m, 4H), 3.54 (d, J = 28.4 Hz, 4H),3.29 (d, J = 65.1 Hz, 2H), 2.96 (s, 3H), 2.15 (dd, J = 58.8, 17.3 Hz,4H). I-N-134 512.2 1.84* ¹H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.54(s, 1H), 9.51 (dd, J = 4.8, 2.5 Hz, 1H), 9.30 (s, 1H), 8.87 (d, J = 2.5Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 6.81 (s, 2H), 3.98-3.81 (m, 4H),3.38-3.25 (m, 6H), 3.09 (t, J = 4.9 Hz, 4H), 2.22-2.11 (m, 6H). I-N-135431.2 1.94* ¹H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.54-9.48 (m,2H), 8.74 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H), 6.80 (s, 2H),4.07 (q, J = 5.3 Hz, 1H), 3.80 (dd, J = 11.4, 2.9 Hz, 1H), 3.64-3.49 (m,2H), 3.29-3.24 (m, 1H), 3.19-3.08 (m, 2H), 2.99 (dm, J = 11.9 Hz, 1H),2.90-2.77 (m, 2H), 2.73 (dm, J = 11.8 Hz, 2H), 2.63-2.57 (m, 1H), 2.41(td, J = 11.6, 3.3 Hz, 1H). I-N-136 427.2 1.12* ¹H NMR (500 MHz,DMSO-d6) δ 9.90 (s, 1H), 9.51 (s, 1H), 9.47 (dd, J = 4.8, 2.5 Hz, 1H),8.99-8.94 (m, 1H), 8.23 (d, J = 5.3 Hz, 1H), 7.21 (d, J = 5.3 Hz, 1H),6.76 (s, 2H), 4.51-4.43 (m, 1H), 4.07 (s, 2H), 3.98 (dd, J = 11.8, 4.7Hz, 1H), 3.96-3.87 (m, 1H), 3.57 (dd, J = 11.8, 7.0 Hz, 1H), 3.25-3.15(m, 2H), 3.04 (td, J = 12.5, 2.9 Hz, 1H), 2.73-2.65 (m, 2H). I-N-137431.2 1.94* ¹H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.54-9.48 (m,2H), 8.74 (d, J = 2.5 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H), 6.80 (s, 2H),4.07 (q, J = 5.3 Hz, 1H), 3.80 (dd, J = 11.4, 2.9 Hz, 1H), 3.64-3.49 (m,2H), 3.29-3.24 (m, 1H), 3.19-3.08 (m, 2H), 2.99 (dm, J = 11.9 Hz, 1H),2.90-2.77 (m, 2H), 2.73 (dm, J = 11.8 Hz, 2H), 2.63-2.57 (m, 1H), 2.41(td, J = 11.6, 3.3 Hz, 1H). I-N-138 438.2 2.21* ¹H NMR (500 MHz,DMSO-d6) δ 1.84 (6H, s), 2.33 (3H, s), 2.64 (4H, br d), 3.11 (4H, br s),6.81 (2H, s), 8.26 (1H, d), 8.815 (1H, d), 9.16 (1H, d), 9.52 (1H, d),10.46 (1H, s). I-N-139 447.1 2.35* — I-N-140 501.1 2.04* ¹H NMR (500MHz, DMSO-d6) δ 2.10-2.15 (3H, s), 2.35-2.40 (2H, m), 2.50-2.60 (2H,masked), 2.66 (2H, br s), 2.81 (4H, br s), 3.15 (2H, br s), 7.51-7.52(1H, d), 7.88-7.89 (1H, s), 8.21-8.23 (1H, d), 8.77 (1H, s). I-N-141357.0 1.89* ¹H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.52 (dd, J = 4.7,2.5 Hz, 1H), 9.31 (d, J = 1.1 Hz, 1H), 8.97 (dd, J = 2.5, 0.5 Hz, 1H),8.47 (dd, J = 6.6, 1.1 Hz, 1H), 7.53 (d, J = 6.6 Hz, 1H), 6.78 (s, 2H),3.86-3.81 (m, 4H), 3.39-3.33 (m, 4H). I-N-142 463.1 1.94* ¹H NMR (500MHz, DMSO-d6) δ 9.69 (s, 1H), 9.34 (s, 1H), 9.13 (d, J = 2.2 Hz, 1H),8.92 (d, J = 2.3 Hz, 1H), 8.56-8.43 (m, 1H), 7.57 (d, J = 6.5 Hz, 1H),6.80 (s, 2H), 4.79-4.59 (m, 4H), 4.20 (s, 1H), 3.57 (d, J = 6.0 Hz, 5H),3.08 (s, 4H), 1.85 (s, 6H). I-N-143 448.2 1.81* ¹H NMR (500 MHz,DMSO-d6) δ 9.71 (s, 1H), 9.32 (d, J = 1.0 Hz, 1H), 9.16 (dd, J = 2.1,0.6 Hz, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.46 (dd, J = 6.5, 1.0 Hz, 1H),7.55 (d, J = 6.4 Hz, 1H), 6.88-6.70 (m, 2H), 4.65-4.69 (m, 5H), 4.51 (q,J = 7.2 Hz, 1H), 3.51 (s, 4H), 2.96 (br s, 3H), 1.71 (d, J = 7.2 Hz,3H). I-N-144 480.2 2.12* ¹H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.45(s, 1H), 9.15 (d, J = 2.2 Hz, 1H), 8.88 (d, J = 2.3 Hz, 1H), 8.33 (d, J= 2.6 Hz, 1H), 6.81 (s, 2H), 4.87-4.67 (m, 4H), 4.42-4.27 (br m, 9H),1.87 (s, 6H). I-N-145 466.1 2.00* ¹H NMR (500 MHz, DMSO-d6) δ 10.20 (s,1H), 9.48 (s, 1H), 9.19 (dd, J = 2.1, 0.6 Hz, 1H), 8.78 (d, J = 2.1 Hz,1H), 8.33 (d, J = 2.5 Hz, 1H), 6.81 (s, 2H), 4.86-4.70 (m, 4H), 4.52 (q,J = 7.2 Hz, 1H), 3.71 (5H), 3.41 (s, 4H), 1.73 (d, J = 7.3 Hz, 3H).I-N-146 481.1 2.44* ¹H NMR (500 MHz, DMSO-d6) δ 2.05-2.12 (4H, m), 2.9(6H, s), 3.15-3.22 (4H, m), 3.55-3.62 (1H, m), 8.29 (1H, d), 8.96 (1H,d), 9.50-9.53 (1H, m), 9.65 (1H, s), 10.42 (1H, s). I-N-147 457.1 2.1* —I-N-148 564.2 2.42* ¹H NMR (500 MHz, DMSO-d6) δ 1.88-1.92 (2H, m),1.96-2.05 (2H, m), 2.06-2.15 (4H, m), 2.77-2.83 (6H, m), 3.1-3.22 (6H,m), 3.47-3.60 (3H, m), 3.85-3.95 (1H, m), 8.29 (1H, d), 8.96 (1H, d),9.40 (1H, s), 9.50-9.53 (1H, m), 9.65 (1H, s), 10.42 (1H, s). I-N-149473.2 2.60* ¹H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.53 (dd, J =4.9, 2.5 Hz, 1H), 9.51 (s, 1H), 9.40 (s, 1H), 8.80 (d, J = 2.5 Hz, 1H),8.28 (d, J = 2.8 Hz, 1H), 6.82 (s, 2H), 4.01 (d, J = 12.9 Hz, 2H), 3.73(t, J = 12.0 Hz, 2H), 3.56 (d, J = 12.4 Hz, 2H), 3.21 (t, J = 6.1 Hz,2H), 3.13 (d, J = 7.7 Hz, 5H), 2.08 (d, J = 5.7 Hz, 2H), 1.90 (d, J =11.8 Hz, 2H), 1.56 (q, J = 18.7, 14.9 Hz, 2H). I-N-150 486.2 2.41* ¹HNMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.52 (dd, J = 4.8, 2.5 Hz, 1H),9.49 (s, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.28 (d, J = 2.9 Hz, 1H), 6.82(s, 2H), 3.47 (br s, 6H), 3.19-2.94 (m, 5H), 2.86-2.78 (m, 2H), 2.82 (s,3H), 1.86 (d, J = 12.8 Hz, 4H), 1.52 (dd, J = 16.7, 8.1 Hz, 2H). I-N-151486.2 1.96* — I-N-152 354.0 2.59* ¹H NMR (500 MHz, DMSO-d6) δ 9.61 (s,1H), 9.52 (dd, J = 4.8, 2.5 Hz, 1H), 9.20 (s, 1H), 8.90 (d, J = 2.5 Hz,1H), 8.38 (d, J = 6.7 Hz, 1H), 7.46 (d, J = 6.6 Hz, 1H), 6.77 (s, 2H),3.32 (t, J = 5.4 Hz, 4H), 1.77-1.69 (m, 4H), 1.65 (td, J = 6.3, 3.5 Hz,2H). I-N-153 460.2 2.01* — I-N-154 469.2 2.16* ¹H NMR (500 MHz, DMSO-d6)δ 1.42-1.50 (2H, m), 1.72-1.81 (4H, m), 1.96-2.04 (5H, m), 2.14 (3H, s),2.61 (2H, m), 2.81 (2H, m), 3.07 (2H, m), 3.40-3.47 (1H, m), 3.67-3.72(1H, m), 6.77 (2H, br s), 7.17 (1H, d), 8.20 (1H, d), 8.73 (1H, d), 9.44(1H, s), 9.49 (1H, m) and 9.91 (1H, br s) ppm. I-N-155 523.2 2.37* ¹HNMR (500 MHz, DMSO-d6) δ 2.02-2.18 (4H, m), 3.12-3.22 (4H, m), 3.26-3.40(8H, m), 3.57-3.63 (1H, m), 3.62-3.68 (4H, m), 8.27 (1H, d), 8.95 (1H,d), 9.48-9.52 (1H, m), 9.64 (1H, s), 10.42 (1H, s). I-N-156 486.2 1.97*¹H NMR (500 MHz, methanol-d4) δ 2.09-2.20 (2H, m), 2.41 (2H, s),2.52-2.57 (1H, m), 2.70-2.82 (2H, m), 2.93-2.97 (1H, m), 3.17-3.22 (3H,m), 3.40-3.45 (1H, m), 3.88-3.97 (1H, m), 8.18 (1H, d), 8.71 (1H, dd),9.58 (1H, s), I-N-157 486.2 2.03* — I-N-158 523.1 2.25* ¹H NMR (500 MHz,CDCl3) δ 1.92-2.05 (3H, m), 2.07-2.12 (2H, m), 3.26-3.28 (4H, m), 3.45(2H, m), 3.61-3.63 (4H, m), 5.89 (2H, s), 8.25 (1H, d), 8.54 (1H, dd),8.61 (1H, d), 9.70 (1H, s), 10.25 (1H, s). I-N-159 479.1 2.34* — I-N-160472.1 1.96* — I-N-161 354.0 1.70* — I-N-162 354.0 1.63* — I-N-163 429.11.93* ¹H NMR (500 MHz, DMSO-d6) δ 1.52-1.62 (2H, m), 1.12-1.18 (1H, m),2.22-2.25 (1H, m), 2.32-2.37 (1H, m), 2.85-2.92 (1H, m), 2.94-2.98 (1H,m), 3.03-3.18 (2H, m), 3.22-3.27 (1H, m), 3.95 (1H, masked), 6.85 (2H,br s), 8.29 (1H, d), 8.81 (1H, d), 9.48 (1H, dd), 9.55 (1H, s), 10.42(1H, s). I-N-164 441.2 2.02* ¹H NMR (500 MHz, DMSO-d6) δ 1.70-1.76 (2H,m), 1.94-1.97 (2H, m), 2.24 (3H, s), 2.75-2.81 (4H, m), 3.04-3.08 (2H,m), 3.53-3.57 (3H, m), 4.10-4.15 (1H, m), 6.77 (2H, br s), 7.18 (1H, d),8.21 (1H, d), 8.75 (1H, d), 9.42 (1H, s), 9.49 (1H, m) and 9.86 (1H, brs) ppm. I-N-165 452.0 1.48* ¹H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H),9.64 (s, 1H), 9.49 (dd, J = 4.7, 2.5 Hz, 1H), 8.96 (d, J = 2.3 Hz, 1H),8.27 (d, J = 2.6 Hz, 1H), 7.16 (s, 1H), 6.80 (s, 2H), 3.45 (ddt, J =12.2, 7.5, 3.8 Hz, 1H), 3.25-3.10 (m, 4H), 3.07 (s, 3H), 2.23-2.16 (m,2H), 2.10-1.98 (m, 2H). I-N-166 536.1 2.33* ¹H NMR (500 MHz, DMSO-d6) δ2.02-2.18 (5H, m), 2.47 (3H, s), 3.12-3.32 (7H, m), 3.48-3.53 (2H, m),3.65-3.71 (1H, m), 3.85-3.92 (4H, m), 8.27 (1H, d), 8.91 (1H, d),9.51-9.53 (1H, m), 9.65 (1H, s), 9.72 (1H, brs), 10.43 (1H, s). I-N-167487.2 2.38* ¹H NMR (500 MHz, methanol-d4) δ 9.60 (s, 1H), 9.05 (dd, J =4.4, 2.5 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.9 Hz, 1H),3.76 (t, J = 5.8 Hz, 2H), 3.65 (dt, J = 9.1, 4.8 Hz, 1H), 3.28-3.22 (m,2H), 3.16 (dt, J = 11.4, 2.6 Hz, 2H), 2.83 (t, J = 5.8 Hz, 2H), 2.72 (d,J = 6.9 Hz, 4H), 2.19 (dt, J = 13.0, 4.0 Hz, 2H), 2.07-1.96 (m, 2H),1.90-1.84 (m, 4H). I-N-168 458.2 1.70* ¹H NMR (500 MHz, DMSO-d6) δ 10.39(s, 1H), 9.56 (s, 1H), 9.51 (dd, J = 4.8, 2.5 Hz, 1H), 8.87 (d, J = 2.5Hz, 1H), 8.62 (s, 1H), 8.29 (d, J = 2.5 Hz, 1H), 6.81 (s, 2H), 4.30-4.08(m, 4H), 4.07-3.92 (m, 1H), 3.77 (s, 2H), 3.08 (dt, J = 10.8, 4.7 Hz,4H). I-N-169 493.1 2.51* ¹H NMR (500 MHz, DMSO-d6) δ 2.01-2.12 (2H, m),2.12-2.18 (2H, m), 2.22-2.28 (2H, m), 3.16-3.21 (4H, m), 3.38-3.46 (1H,m), 3.92-3.97 (4H, m), 5.8 (2H, brs), 8.29 (1H, d), 8.93 (1H, d),9.50-9.53 (1H, m), 9.63 (1H, s), 10.41 (1H, s). I-N-170 505.1 2.12* ¹HNMR (500 MHz, DMSO-d6) δ 2.02-2.18 (3H, m), 2.98-3.08 (2H, m), 3.25-3.31(4H, m), 3.57-3.71 (8H, m), 6.82 (2H, brs), 7.5 (1H, d), 8.42 (1H, d),8.81 (1H, d), 9.44 (1H, s), 9.54-9.57 (1H, m), 9.80 (1H, s). I-N-171500.1 2.31* ¹H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.57-9.47 (m,2H), 8.80 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 6.82 (s, 2H),4.12 (s, 2H), 3.86 (s, 2H), 3.56 (s, 2H), 3.42 (s, 1H), 3.24 (s, 1H),3.12 (s, 4H), 2.92 (s, 3H), 2.11 (s, 1H), 1.88 (s, 2H), 1.63-1.45 (m,2H). I-N-172 488.1 1.8* — I-N-173 501.0 2.26* — I-N-174 502.2 1.94* ¹HNMR (500 MHz, DMSO-d6) δ 2.15-2.30 (4H, m), 2.65-2.75 (1H, br s),2.78-2.88 (1H, br s), 3.02-3.14 (5H, m), 3.55-3.65 (2H, br s), 3.70-3.75(1H, br s), 3.82-3.90 (3H, br s), 4.30-4.38 (1H, br s), 6.80 (2H, s),8.27 (1H, d), 8.82 (1H, d), 9.49 (1H, dd), 9.55 (1H, d), 10.40 (1H, s).I-N-175 536.0 2.26* — I-N-176 461.0 2.14* ¹H NMR (500 MHz, DMSO-d6) δ0.94-1.03 (4H, m), 2.80-2.83 (1H, m), 3.37 (4H, m), 3.42 (4H, m), 6.79(2H, s), 7.51-7.52 (1H, d), 8.44-8.45 (1H, d), 8.88 (1H, d), 9.32 (1H,s), 9.55 (1H, dd), 9.77 (1H, s). I-N-177 505.0 2.08* — I-N-178 435.01.9* — I-N-179 491.0 2.03* — I-N-180 478.0 1.87* ¹H NMR (500 MHz,DMSO-d6) δ 1.66-1.70 (2H, m), 1.80-1.85 (2H, m), 2.59 (4H, brs), 3.12(4H, brs), 3.58-3.64 (1H, m), 4.48-4.52 (2H, m), 3.58-3.62 (2H, m), 6.78(2H, s), 8.24 (1H, s), 8.71 (1H, s), 9.08 (1H, s), 9.49 (1H, s), 10.36(1H, s). I-N-181 486.0 2.07* ¹H NMR (500 MHz, DMSO-d6) δ 1.85-2.03 (2H,m), 2.06-2.13 (1H, m), 2.86 (3H, d), 3.11-3.13 (4H, m), 3.19-3.24 (1H,m), 3.63-3.68 (3H, m), 3.75-3.80 (1H, m), 3.82-3.85 (1H, m), 4.63-4.65(2H, m), 6.80 (2H, br s), 8.30 (1H, d), 8.90 (1H, d), 9.51-9.53 (1H,dd), 9.56 (2H, m), 10.37 (1H, s). I-N-182 429.0 1.97* ¹H NMR (500 MHz,DMSO-d6) δ 1.52-1.62 (2H, m), 1.12-1.18 (1H, m), 2.22-2.25 (1H, m),2.32-2.37 (1H, m), 2.85-2.92 (1H, m), 2.94-2.98 (1H, m), 3.03-3.18 (2H,m), 3.22-3.27 (1H, m), 3.95 (1H, masked), 6.85 (2H, br s), 8.29 (1H, d),8.81 (1H, d), 9.48 (1H, dd), 9.55 (1H, s), 10.42 (1H, s). I-N-183 441.42.12* ¹H NMR (500 MHz, DMSO-d6) δ 1.77-1.82 (2H, m), 1.99 (2H, m), 2.23(3H, m), 2.37 (3H, m), 2.93 (4H, m), 3.68 (2H, m), 6.77 (2H, br s), 7.19(1H, d, J = 5Hz), 8.20 (1H, d), 8.80 (1H, m), 9.41 (1H, s), 9.41 (1H, m)and 9.79 (1H, br s) ppm. I-N-184 457.1 2.74* ¹H NMR (500 MHz, DMSO-d6) δ10.52 (s, 1H), 9.60 (s, 1H), 9.49 (dd, J = 4.7, 2.5 Hz, 1H), 8.99 (dd, J= 2.6, 0.7 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.83 (d, J = 3.3 Hz, 1H),7.68 (d, J = 3.3 Hz, 1H), 6.80 (s, 2H), 3.40-3.32 (m, 1H), 3.27-3.22 (m,2H), 3.16 (d, J = 11.7 Hz, 2H), 2.30-2.20 (m, 2H), 2.12 (d, J = 12.5 Hz,2H). I-N-185 500.0 2.16* — I-N-186 429.0 1.97* ¹H NMR (500 MHz, DMSO-d6)δ 1.52-1.62 (1H, m), 2.11-2.17 (1H, m), 2.22-2.25 (1H, m), 2.32-2.37(1H, m), 2.85-2.88 (1H, m), 2.90-2.92 (1H, m), 3.02-3.05 (1H, m),3.10-3.13 (1H, m), 3.22-3.27 (1H, m), 3.93-3.95 (2H, m), 6.79 (2H, brs), 8.29 (1H, d), 8.81 (1H, d), 9.48 (1H, dd), 9.55 (1H, s), 10.42 (1H,s). I-N-187 486.0 2.19* ¹H NMR (500 MHz, CDCl3) δ 10.34 (s, 1H), 9.69(s, 1H), 8.54-8.55 (dd, 1H), 8.46 (d, 1H), 8.23 (d, 1H), 5.89 (s, 2H),3.90 (s, 4H), 3.48 (s, 2H), 3.18 (s, 4H), 2.71 (s, 4H). 1.86 (s, 4H).I-N-188 518.0 2.05* ¹H NMR (500 MHz, DMSO-d6) δ 1.80-1.87 (2H, m),2.20-2.25 (2H, m), 2.81 (3H, s), 2.92-2.97 (2H, m), 3.33 (3H, s),3.48-3.56 (8H, m), 6.80 (2H, s), 7.45 (1H, m), 8.41 (1H, d), 8.90 (1H,d), 9.31 (1H, s), 9.53-9.55 (1H, d), 9.73 (1H, s). I-N-189 459.0 2.36*¹H NMR (500 MHz, DMSO-d6) δ 1.85-1.88 (2H, m), 2.17-2.19 (2H, m),3.14-3.21 (3H, m), 3.27-3.30 (2H, m), 3.53-3.55 (2H, m), 3.73-3.76 (2H,m), 4.04-4.07 (2H, m), 6.75-6.6.85 (2H, s), 7.41-7.44 (1H, m), 7.54-7.56(1H, m), 7.72-7.74 (1H, d), 7.99-8.00 (1H, d), 8.29 (1H, d), 8.94 (1H,d), 9.41 (1H, s), 9.52-9.54 (1H, m), 9.60-9.80 (1H, m), 10.05 (1H, s).I-N-190 434.0 0.6 ¹H NMR (500 MHz, Methanol-d4) δ 9.90 (s, 0.5H), 9.62(d, 1H), 9.1-9.07 (m, 1H), 8.88 (d, 1H), 8.38 (d, 1H), 7.62 (d, 1H),3.92-3.85 (m, 2H), 3.51-3.45 (m, 1H), 3.15-3.08 (m, 2H), 3.06 (s, 3H),2.35-2.26 (m, 4H) I-N-191 486.2 1.89* — I-N-192 533.0 2.44* ¹H NMR (500MHz, DMSO-d6) δ 10.37 (1H, s), 9.48 (1H, s), 9.08 (1H, d), 8.68 (1H, d),8.28 (1H, d), 6.77 (2H, brs), 3.08-3.19 (6H, m), 2.80 (3H, s), 1.85-1.88(2H, m), 1.76-1.81 (2H, m), 1.70-1.73 (2H, m), 1.52-1.55 (2H, m) (n.bsome signals masked by broad water peak). I-N-193 500.1 2.24* ¹H NMR(500 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.53 (s, 1H), 9.51 (dd, J = 4.7, 2.5Hz, 1H), 8.94 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 6.81 (s,2H), 3.92 (s, 2H), 3.59 (d, J = 4.7 Hz, 4H), 3.45 (s, 2H), 3.17-3.00 (m,4H), 2.88 (s, 3H), 1.93 (dtd, J = 15.7, 8.3, 7.6, 3.8 Hz, 1H), 1.74 (d,J = 12.1 Hz, 2H), 1.55 (qd, J = 12.1, 4.4 Hz, 2H). I-N-194 472.1 1.85*¹H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.04-9.05 (dd, 1H), 9.70 (d,1H), 8.18 (d, 1H), 3.92 (s, 2H), 3.68-3.71 (m, 5H), 3.49 (m, 2H),3.18-3.20 (m, 4H), 2.42 (s, 3H). I-N-195 477.1 1.97* ¹H NMR (500 MHz,DMSO-d6) δ 9.80 (s, 1H), 9.50-9.51 (dd, 1H), 9.39 (s, 1H), 8.91 (d, 1H),8.26 (d, 1H), 7.23-7.24 (d, 1H), 6.76 (s, 2H), 4.93-4.97 (m, 1H),4.84-4.88 (m, 2H), 4.73-4.76 (m, 2H), 3.35 (s, 4H), 3.03 (s, 4H).I-N-196 544.1 2.04* ¹H NMR (500 MHz, DMSO-d6) δ 1.97-2.18 (9H, m),2.92-3.00 (2H, m), 3.30-3.50 (5H, m), 3.55-3.65 (3H, m), 3.67-3.72 (2H,m), 4.22-4.26 (1H, m), 6.70-6.88 (2H, m), 7.45 (1H, d), 8.40 (1H, d),8.78 (1H, s), 9.45 (1H, s), 9.52-9.54 (1H, m), 9.8 (1H, brs), 10.35 (1H,s). I-N-197 475.1 2.83* ¹H NMR (500 MHz, Methanol-d4) δ 9.69 (s, 1H),9.20 (dd, 1H), 9.11 (dd, 1H), 8.76 (dd, 1H), 8.36-8.22 (m, 1H), 7.51(dd, 1H), 3.98 (d, 2H), 3.71 (br t, 2H), 3.52 (s, 2H), 3.19-3.16 (m,2H), 3.13 (dd, 2H), 2.59 (tt, 2H), 2.11-2.05 (m, 1H), 1.98 (d, 2H), 1.62(qd, 2H). I-N-198 468.1 1.83* ¹H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H),9.46-9.49 (m, 2H), 8.94 (d, 1H), 7.20 (d, 1H), 6.76 (s, 2H), 3.90-3.95(m, 1H), 3.80-3.87 (m, 2H), 3.60-3.67 (m, 1H), 3.29 (s, 3H), 3.15-3.25(m, 1H), 2.85-3.00 (m, 4H), 2.20-2.30 (m, 2H), 2.10-2.15 (m, 1H),1.80-1.90 (m, 2H). I-N-199 468.2 1.83* ¹H NMR (500 MHz, DMSO-d6) δ 9.88(s, 1H), 9.46-9.49 (m, 2H), 8.94 (d, 1H), 7.20 (d, 1H), 6.76 (s, 2H),3.90-3.95 (m, 1H), 3.80-3.87 (m, 2H), 3.60-3.67 (m, 1H), 3.29 (s, 3H),3.15-3.25 (m, 1H), 2.85-3.00 (m, 4H), 2.20-2.30 (m, 2H), 2.10-2.15 (m,1H), 1.80-1.90 (m, 2H). I-N-200 476.1 1.9* ¹H NMR (500 MHz, DMSO-d6) δ1.97-2.12 (4H, m), 2.92-3.00 (2H, m), 3.44-3.56 (1H, m), 3.60-3.67 (2H,m), 4.75-4.79 (2H, m), 4.83-4.86 (2H, m), 6.80 (2H, brs), 7.50 (1H, d),8.42 (1H, d), 8.81-8.83 (1H, m), 9.47 (1H, s), 9.54-9.58 (1H, m), 9.8(1H, brs). I-N-201 495.0 2.13* ¹H NMR (500 MHz, DMSO-d6) δ 10.24 (s,1H), 9.52 (dd, J = 4.8, 2.5 Hz, 1H), 9.46 (s, 1H), 8.84-8.80 (m, 1H),8.30 (d, J = 2.6 Hz, 1H), 6.79 (s, 2H), 5.07-4.97 (m, 1H), 4.85 (dd, J =8.1, 7.0 Hz, 2H), 4.75 (dd, J = 7.1, 6.1 Hz, 2H), 3.45 (dd, J = 6.1, 3.4Hz, 4H), 3.18-3.12 (m, 4H). I-N-202 379.1 1.88* ¹H NMR (500 MHz,DMSO-d6) δ 9.80 (s, 1H), 9.49 (dd, J = 4.8, 2.5 Hz, 1H), 9.42 (s, 1H),8.61 (d, J = 5.1 Hz, 1H), 8.39 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 18.1,2.1 Hz, 2H), 7.79 (d, J = 5.1 Hz, 1H), 6.74 (s, 2H), 1.87 (ddd, J =10.6, 8.2, 5.3 Hz, 1H), 1.11-0.93 (m, 4H). I-N-203 526.1 2.26* — I-N-204514.0 2.41* ¹H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.55 (s, 1H),9.51-9.52 (dd, 1H), 9.38-9.46 (m, 1H), 8.88 (d, 1H), 8.30 (d, 1H), 6.80(s, 2H), 4.56-4.61 (m, 1H), 3.92-3.95 (m, 1H), 3.82-3.85 (m, 1H),3.70-3.80 (m, 2H), 3.55-3.58 (m, 1H), 3.08-3.20 (m, 5H), 2.98-3.05 (m,1H), 2.89-2.95 (m, 1H), 212-2.15 (m, 1H), 1.78-1.90 (m, 3H), 1.50-1.65(m, 2H), .25-1.28 (t, 3H). I-N-205 514.0 2.23* — I-N-206 514.1 2.18* —I-N-207 500.1 2.09* — I-N-208 478.2 2.04* ¹H NMR (500 MHz, DMSO-d6) δ1.99-2.10 (2H, m), 2.18-2.25 (2H, m), 2.95-3.05 (2H, m), 3.32 (3H, s),3.40-3.50 (4H, m), 3.62-3.68 (2H, m), 3.75-3.78 (2H, m), 6.80 (2H, brs),7.55 (1H, d), 8.43 (1H, d), 8.81-8.82 (1H, m), 9.48 (1H, s), 9.54-9.57(1H, m), 9.8 (1H, brs). I-N-209 385.1 1.61* ¹H NMR (500 MHz, DMSO-d6) δ9.62 (s, 1H), 9.53 (dd, 1H), 9.09 (s, 1H), 8.74 (d, 1H), 8.40 (dd, 1H),7.42 (d, 1H), 6.75 (s, 2H), 4.02 (s, 2H), 3.75 (br t, 2H), 3.48 (br t,1H), 2.94 (s, 3H). I-N-210 406.0 1.65* ¹H NMR (500 MHz, DMSO-d6) δ 9.77(s, 1H), 9.55 (dd, J = 4.8, 2.5 Hz, 1H), 9.33 (d, J = 0.9 Hz, 1H),8.86-8.81 (m, 1H), 8.47 (dd, J = 6.2, 0.9 Hz, 1H), 7.64 (d, J = 6.3 Hz,1H), 6.80 (s, 2H), 3.77-3.71 (m, 4H), 3.46-3.40 (m, 8H). I-N-211 542.12.02* I-N-212 403.1 1.8* ¹H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.51(s, 1H), 9.50 (t, 1H), 8.54 (d, 1H), 8.31 (d, 1H), 6.76 (br s, 2H), 3.71(s, 2H), 3.53-3.50 (m, 2H), 3.46-3.44 (m, 2H), 3.01 (s, 3H). I-N-213471.1 2.44* ¹H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.52 (s, 1H),9.50 (dd, 1H), 8.99 (d, 1H), 8.28 (d, 1H), 6.79 (br s, 2H), 3.38 (t,2H), 3.22 (d, 2H), 3.12-3.02 (m, 4H), 2.26 (t, 2H), 1.98-1.92 (m, 2H),1.89-1.82 (m, 1H), 1.68 (dd, 2H), 1.52 (qd, 2H). I-N-214 500.1 2.49* ¹HNMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.49-9.56 (m, 2H), 8.77 (d, 1H),8.27 (d, 1H), 6.80 (s, 2H), 4.02-4.25 (m, 2H), 3.80-3.90 (m, 1H),3.70-3.80 (m, 2H), 3.35-3.45 (m, 1H), 3.05-3.20 (m, 4H), 2.88-2.90 (m,1H), 2.19 (s, 2H), 1.90-205 (m, 2H), 1.60-1.80 (m, 3H), 1.50-1.55 (s,1H), 1.30-1.40 (m, 1H). I-N-215 448.1 1.91* ¹H NMR (500 MHz, DMSO-d6) δ1.62-1.70 (2H, m), 1.96-2.03 (2H, m), 2.20-2.28 (1H, m), 3.00-3.08 (5H,m), 3.28 (2H, d), 3.62-3.68 (2H, m), 6.80 (2H, brs), 7.48 (1H, d), 8.42(1H, d), 8.97 (1H, d), 9.32 (1H, s), 9.53-9.56 (1H, m), 9.63 (1H, brs).I-N-216 441.0 1.95* ¹H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.53 (dd,1H), 9.29 (s, 1H), 8.88 (d, 1H), 8.43-8.45 (dd, 1H), 7.57-7.58 (d, 1H),6.79 (s, 2H), 3.45-3.50 (m, 2H), 3.45 (s, 2H), 3.30-3.45 (m, 2H), 2.78(s, 3H), 1.97-2.08 (m, 4H). I-N-217 411.1 1.74* ¹H NMR (500 MHz,DMSO-d6) δ 9.78 (s, 1H), 9.52 (dd, J = 4.8, 2.5 Hz, 1H), 9.40-9.34 (m,1H), 8.99-8.92 (m, 1H), 8.43 (dd, J = 6.3, 0.9 Hz, 1H), 7.52 (d, J = 6.4Hz, 1H), 6.78 (s, 2H), 3.95-3.85 (m, 2H), 3.77-3.70 (m, 1H), 3.62 (d, J= 12.5 Hz, 1H), 3.15-3.05 (m, 1H), 2.87 (td, J = 12.3, 3.5 Hz, 1H), 2.77(dd, J = 12.1, 10.9 Hz, 1H), 2.37-2.21 (m, 2H), 2.09 (dddd, J = 12.8,9.8, 7.7, 4.0 Hz, 1H), 1.63-1.52 (m, 1H). I-N-218 368.1 1.66* ¹H NMR(500 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.73 (s, 1H), 9.45 (dd, J = 4.8, 2.5Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.46 (d, J = 2.5 Hz, 1H), 7.67 (dd, J= 5.1, 0.6 Hz, 1H), 2.38 (s, 3H), 2.36 (s, 3H). I-N-219 407.0 2.1* ¹HNMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.48 (s, 1H), 9.45 (dd, J = 4.8,2.5 Hz, 1H), 8.52 (d, J = 5.0 Hz, 1H), 8.24 (d, J = 2.5 Hz, 1H), 7.87(d, J = 1.3 Hz, 1H), 7.71 (d, J = 5.1 Hz, 1H), 7.59 (d, J = 1.3 Hz, 1H),6.66 (s, 2H). I-N-220 370.1 2.63* ¹H NMR (500 MHz, DMSO-d6) δ 9.48 (dd,J = 4.8, 2.6 Hz, 1H), 9.26 (d, J = 0.9 Hz, 1H), 8.79 (d, J = 2.5 Hz,1H), 8.30 (dd, J = 1.5, 0.7 Hz, 1H), 8.10 (dd, J = 7.4, 1.4 Hz, 1H),7.30 (d, J = 7.4 Hz, 1H), 6.65 (s, 2H), 3.80 (t, J = 6.5 Hz, 2H),1.90-1.77 (m, 4H), 1.54 (s, 6H). I-N-221 434.0 1.88* ¹H NMR (500 MHz,DMSO-d6) δ 9.69 (1H, s), 9.53 (1H, dd), 9.35 (1H, s), 9.00 (1H, dd),8.45 (1H, dd), 7.57 (1H, d), 6.79 (2H, brs), 3.92 (1H, d), 3.52-3.58(2H, m), 3.16-3.21 (1H, t), 2.99 (3H, s), 2.88-2.93 (1H, m), 2.30-2.33(1H, m), 1.83-1.93 (2H, m), 1.67-1.71 (1H, m). I-N-222 411.1 1.8* ¹H NMR(500 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.52 (dd, 1H), 9.01 (s, 1H), 8.74 (d,1H), 8.38 (dd, 1H), 7.44 (d, 1H), 6.74 (s, 2H), 4.24 (d, 1H), 4.20 (d,1H), 3.87 (d, 1H), 3.84-3.78 (m, 1H), 3.53-3.48 (m, 1H), 3.41-3.36 (m,1H), 3.18 (dd, 1H), 1.95-1.90 (m, 2H), 1.84-1.74 (m, 1H), 1.47-1.38 (m,1H). I-N-223 353.1 1.97* ¹H NMR (500 MHz, DMSO-d6) δ 2.26 (3H, s), 6.47(1H, m), 6.70 (2H, br s), 7.59 (1H, m), 7.94 (1H, m), 8.48 (1H, m), 8.60(1H, m), 9.41 (1H, m), 9.79 (1H, s) and 10.14 (1H, s) ppm. I-N-224 425.11.81* ¹H NMR (500 MHz, DMSO-d6) δ 9.51 (dd, J = 4.8, 2.5 Hz, 1H), 9.45(s, 1H), 8.92 (d, J = 1.1 Hz, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.33 (dd, J= 6.9, 1.2 Hz, 1H), 7.45 (d, J = 6.9 Hz, 1H), 6.73 (s, 2H), 3.97-3.90(m, 1H), 3.72-3.63 (m, 1H), 3.50 (ddd, J = 13.8, 11.4, 5.6 Hz, 2H), 3.10(ddd, J = 13.4, 10.7, 2.7 Hz, 1H), 3.00 (dd, J = 9.9, 1.7 Hz, 1H), 2.74(d, J = 0.7 Hz, 3H), 2.71 (dt, J = 7.5, 4.1 Hz, 1H), 2.63-2.53 (m, 1H),1.94-1.84 (m, 1H), 1.59 (dtd, J = 13.7, 10.1, 3.6 Hz, 1H). I-N-225 352.92.07* ¹H NMR (500 MHz, DMSO-d6) δ 2.32 (3H, s), 6.46 (1H, m), 6.73 (2H,br s), 7.64 (1H, m), 8.37-8.40 (2H, m), 8.76 (1H, m), 9.40-9.42 (2H, m)and 11.10 (1H, s) ppm. I-N-226 398.1 2.0* ¹H NMR (500 MHz, DMSO-d6) δ9.81 (s, 1H), 9.47 (dd, J = 4.8, 2.5 Hz, 1H), 9.44 (s, 1H), 8.77 (d, J =2.5 Hz, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.14 (d, J = 5.3 Hz, 1H), 6.77(s, 2H), 4.39 (s, 4H), 2.86-2.80 (m, 4H), 2.02 (t, J = 5.5 Hz, 4H).I-N-227 502.0 1.99* ¹H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.20 (s,1H), 9.56 (s, 1H), 9.51 (dd, 1H), 8.91 (d, 1H), 8.30 (d, 1H), 6.80 (brs, 2H), 4.80-4.85 (m, 1H), 4.32 (m, 1H), 4.01-4.09 (m, 2H), 3.88-3.91(m, 1H), 3.70-3.76 (m, 2H), 3.57-3.62 (m, 1H), 3.49-3.53 (t, 1H),3.42-3.45 (d, 1H), 3.20 (m, 3H), 3.11 (s, 2H), 2.83 (s, 3H). I-N-228472.0 2.06* ¹H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.52-9.54 (m,2H), 9.07 (dd, 1H), 8.32 (d, 1H), 6.80 (br s, 2H), 4.22-4.24 (m, 2H),4.15 (s, 2H), 3.99-4.00 (t, 2H), 3.25-3.70 (m, 8H), 2.29-237 (s, 2H).I-N-229 459.0 2.18* ¹H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.51-9.52(dd, 2H), 8.67 (d, 1H), 8.30 (d, 1H), 6.80 (br s, 2H), 3.54 (s, 2H),3.22-3.28 (m, 2H), 3.02-3.08 (m, 2H), 2.81 (s, 3H), 2.02-2.07 (m, 4H).I-N-230 439.0 1.92* ¹H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.49 (dd,J = 4.8, 2.5 Hz, 1H), 9.36 (s, 1H), 8.93-8.88 (m, 1H), 8.22 (d, J = 5.3Hz, 1H), 7.19 (d, J = 5.4 Hz, 1H), 6.76 (d, J = 4.5 Hz, 2H), 4.34 (t, J= 5.1 Hz, 1H), 3.84 (tt, J = 12.1, 3.9 Hz, 1H), 3.48-3.44 (m, 1H),3.27-3.21 (m, 2H), 2.80 (td, J = 12.2, 2.2 Hz, 2H), 2.25 (dd, J = 8.6,7.5 Hz, 2H), 2.09-1.91 (m, 4H), 1.69-1.62 (m, 2H). I-N-231 453.1 2.01*1H NMR (500 MHz, DMSO-d6) δ 9.52-9.55 (m, 2H), 9.15 (d, 1H), 8.90 (d,1H), 8.41-8.43 (m, 1H), 7.50 (d, 1H), 6.77 (s, 2H), 3.40 (m, 4H), 3.23(s, 2H), 2.80 (s, 3H), 2.20-2.25 (m, 2H), 1.74-1.77 (m, 2H), 1.63-1.71(m, 4H). I-N-232 429.1 2.02* ¹H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H),9.54 (s, 1H), 9.50 (dd, 1H), 8.48 (d, 1H), 8.30 (d, 1H), 6.76 (s, 2H),3.78-3.56 (m, 5H), 3.50-3.45 (m, 1H), 3.29-3.23 (m, 1H), 2.02-1.94 (m,2H), 1.92-1.84 (m, 1H), 1.54-1.45 (m, 1H). I-N-233 440.1 1.7* ¹H NMR(500 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.52-9.53 (dd, 1H), 9.32 (d, 1H),8.93 (d, 1H), 8.47-8.48 (dd, 1H), 7.57-7.58 (d, 1H), 6.80 (s, 2H),4.03-4.06 (dd, 1H), 3.66-3.69 (m, 1H), 3.45-3.50 (m, 1H), 3.23-3.26 (m,1H), 3.06-3.15 (m, 4H), 2.97-3.03 (m, 1H), 2.95-2.97 (m, 4H), 2.62-2.65(m, 1H). I-N-234 429.1 1.75* ¹H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H),9.52-9.53 (dd, 1H), 9.24 (d, 1H), 8.96-8.97 (dd, 1H), 8.40-8.42 (dd,1H), 7.51-7.52 (d, 1H), 6.80 (s, 2H), 4.51-4.54 (dd, 1H), 3.96-3.98 (m,1H), 3.56-3.58 (m 2H), 3.18-3.23 (m, 2H), 3.02 (s, 3H), 2.77 (s, 3H).I-N-235 439.1 1.83* ¹H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.50 (dd,J = 4.8, 2.5 Hz, 1H), 9.26 (s, 1H), 8.85 (dd, J = 2.6, 0.5 Hz, 1H), 8.23(d, J = 5.3 Hz, 1H), 7.21 (dd, J = 5.3, 0.5 Hz, 1H), 6.77 (s, 2H),3.23-3.16 (m, 2H), 2.89 (dd, J = 13.1, 11.0 Hz, 2H), 2.72 (t, J = 0.7Hz, 3H), 2.26 (dd, J = 8.4, 7.4 Hz, 2H), 2.14 (td, J = 12.7, 4.2 Hz,2H), 1.97 (t, J = 7.9 Hz, 2H), 1.47 (d, J = 12.4 Hz, 2H). I-N-236 439.11.88* ¹H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.53 (dd, J = 4.8, 2.5Hz, 1H), 9.21 (d, J = 1.1 Hz, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.42 (dd, J= 6.7, 1.1 Hz, 1H), 7.51 (d, J = 6.7 Hz, 1H), 6.78 (s, 2H), 3.41-3.32(m, 4H), 3.27 (s, 2H), 2.73 (s, 3H), 2.29 (d, J = 1.1 Hz, 2H), 1.77(dtdd, J = 17.2, 10.7, 7.1, 3.8 Hz, 4H). I-N-237 367.1 2.11* — I-N-238413.1 1.72* ¹H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.53 (dd, J = 4.7,2.5 Hz, 1H), 9.47-9.40 (m, 1H), 9.00 (dd, J = 2.6, 0.6 Hz, 1H), 8.45(dd, J = 6.2, 0.9 Hz, 1H), 7.52 (d, J = 6.2 Hz, 1H), 6.78 (s, 2H),4.42-4.34 (m, 1H), 4.18 (dddd, J = 10.9, 8.6, 5.0, 3.7 Hz, 1H),3.98-3.94 (m, 1H), 3.75-3.64 (m, 2H), 3.52 (d, J = 12.4 Hz, 1H), 3.35(ddd, J = 13.3, 12.0, 3.5 Hz, 1H), 3.02-2.89 (m, 2H). I-N-239 416.12.27* ¹H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.49 (q, J = 2.3 Hz,2H), 8.61 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 3.0 Hz, 1H), 6.79 (s, 2H),4.44 (s, 4H), 3.00 (dd, J = 6.8, 4.1 Hz, 4H), 2.04 (t, J = 5.4 Hz, 4H).I-N-240 458.1 1.88* ¹H NMR (500 MHz, Methanol-d4) δ 9.48 (s, 1H0,9.07-9.09 (d, 1H), 8.77 (d, 1H), 8.43-8.44 (d, 1H), 3.91-3.96 (m, 1H),3.62-3.68 (m, 1H), 3.53-3.56 (m, 1H), 3.30-3.45 (m, 4H), 3.25-3.28 (m,1H), 2.88-3.04 (m, 5H). I-N-241 424.1 2.24* ¹H NMR (500 MHz, DMSO-d6) δ2.05-2.15 (4H, m), 3.15-3.20 (2H, m), 3.23-3.32 (1H, m), 3.62-3.68 (2H,m), 6.80 (2H, brs), 7.52 (1H, d), 8.42 (1H, d), 8.87 (1H, d), 9.38 (1H,s), 9.53-9.56 (1H, m), 9.63 (1H, brs), 9.79 (1H, s). I-N-242 372.0 1.85*— I-N-243 448.0 1.96* ¹H NMR (500 MHz, DMSO-d6) δ 9.71 (1H, s), 9.54(1H, dd), 9.44 (1H, s), 8.88 (1H, d), 8.50 (1H, dd), 7.62 (1H, d), 6.81(2H, brs), 3.59-3.63 (2H, m), 3.17-3.22 (2H, m), 2.97 (3H, s), 2.37-2.42(2H, m), 1.78-1.81 (2H, m), 1.53 (3H, s). I-N-244 425.0 1.93* ¹H NMR(500 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.52-9.53 (dd, 1H), 9.34 (s, 1H),8.99 (d, 1H), 8.43-8.44 (d, 1H), 7.50-7.52 (d, 1H), 6.78 (s, 2H),4.47-4.50 (m, 1H), 3.62-3.78 (m, 2H), 2.94-2.97 (m, 2H), 2.86 (t, 1H),2.18-2.22 (m, 2H), 2.81-2.83 (m, 1H), 2.64-2.78 (m, 2H), 1.35-1.47 (m,1H). I-N-245 468.1 2.05* ¹H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H),9.51-9.53 (dd, 1H), 9.31 (d, 1H), 8.94 (d, 1H), 8.44-8.45 (dd, 1H),7.54-7.55 (d, 1H), 4.50-4.55 (m, 1H) 3.91-3.96 (m, 1H), 3.62-3.68 (m,1H), 3.25-3.30 (m, 1H), 2.90-3.15 (m, 4H), 2.50-2.80 (m, 4H). 1.03-1.06(t, 6H). I-N-246 360.1 2.44* ¹H NMR (500 MHz, DMSO-d6) δ 1.82-1.92 (4H,m), 3.6-3.7 (4H, m), 6.85 (2H, s), 8.45 (1H, d), 8.59 (1H, s), 8.80-8.82(1H, m), 9.48-9.53 (2H, m). I-N-247 447.1 1.89* ¹H NMR (500 MHz,DMSO-d6) δ 9.86 (s, 1H), 9.54 (dd, J = 4.8, 2.5 Hz, 1H), 9.48 (s, 1H),8.74 (d, J = 2.5 Hz, 1H), 8.44 (dd, J = 6.1, 0.7 Hz, 1H), 7.54 (d, J =6.1 Hz, 1H), 6.81 (s, 2H), 3.70-3.63 (m, 1H), 3.57 (d, J = 12.1 Hz, 1H),3.47 (tdd, J = 9.8, 6.7, 3.0 Hz, 1H), 3.40-3.33 (m, 2H), 3.33-3.29 (m,1H), 3.12 (td, J = 11.5, 3.0 Hz, 1H), 3.02 (td, J = 12.0, 3.0 Hz, 1H),2.95 (dd, J = 12.0, 10.2 Hz, 1H), 2.36 (dddd, J = 12.6, 9.3, 5.8, 3.6Hz, 1H), 1.97 (dtd, J = 12.5, 10.3, 8.2 Hz, 1H). I-N-248 431.0 1.91* ¹HNMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.55 (s, 1H), 9.50 (dd, J = 4.8,2.5 Hz, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 6.79(s, 2H), 4.43 (t, J = 8.6 Hz, 1H), 4.20 (ddd, J = 12.1, 9.5, 4.4 Hz,1H), 3.99 (dd, J = 8.9, 5.0 Hz, 1H), 3.73 (dt, J = 13.0, 2.6 Hz, 1H),3.42-3.31 (m, 1H), 3.23 (dd, J = 11.4, 3.9 Hz, 1H), 3.07-2.99 (m, 3H).I-N-249 441.0 1.76* — I-N-250 424.0 1.90* ¹H NMR (500 MHz, DMSO-d6) δ10.32 (s, 1H), 9.58 (s, 1H), 9.55 (dd, J = 4.7, 2.5 Hz, 1H), 8.68 (d, J= 2.5 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 6.85 (s, 2H), 3.60-3.42 (m,8H). I-N-251 439.0 1.94* ¹H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H),9.47-9.48 (dd, 1H), 9.45 (s, 1H), 8.80 (d, 1H), 8.22 (d, 1H), 7.17 (d,1H), 6.77 (s, 2H), 3.93 (s, 2H), 3.63 (s, 2H), 2.87 (m, 4H), 1.93-1.95(m, 4H), 1.78 (s, 3H). I-N-252 434.1 1.91* ¹H NMR (500 MHz, DMSO-d6) δ9.55 (dd, J = 4.7, 2.5 Hz, 1H), 9.51 (s, 1H), 9.26 (s, 1H), 8.66 (d, J =2.5 Hz, 1H), 8.41 (d, J = 6.1 Hz, 1H), 7.54 (d, J = 6.2 Hz, 1H), 6.81(s, 2H), 3.51 (m, 6H), 1.46 (s, 6H). I-N-253 397.9 2.05* ¹H NMR (500MHz, DMSO-d6) δ 9.51-9.52 (d, 1H), 9.48 (s, 1H), 9.25 (s, 1H), 8.83 (d,1H), 7.51-7.53 (d, 1H), 6.78 (s, 2H), 4.43 (d, 2H), 4.31 (d, 2H), 3.55(s, 2H), 3.08 (m, 2H), 1.87-1.89 (m, 2H), 1.65-1.67 (m, 2H). I-N-254399.1 1.72* — I-N-255 411.2 1.8* ¹H NMR (500 MHz, DMSO-d6) δ 9.62 (s,1H), 9.54 (dd, 1H), 9.27 (s, 1H), 8.90 (d, 1H), 8.88 (br s, 2H), 8.40(dd, 1H), 7.46 (d, 1H), 6.80 (s, 2H), 3.34-3.25 (m, 6H), 3.12 (t, 2H),1.91 (t, 2H), 1.83-1.73 (m, 4H). I-N-256 439.1 1.89* 1H NMR (500 MHz,DMSO-d6) (TFA salt) δ 2.37 (3H, s), 3.43-3.48 (4H, m), 3.63-3.67 (4H,m), 6.80 (2H, brs), 7.57 (1H, d), 8.48 (1H, d), 9.02 (1H, d), 9.37 (1H,s), 9.53-9.56 (1H, m), 9.63 (1H, brs), 9.77 (1H, s). I-N-257 453.1 2.05*¹H NMR (500 MHz, DMSO) δ 9.60 (d, 1H), 9.53 (ddd, 1H), 9.19 (t, 1H),8.90 (t, 1H), 8.41 (dt, 1H), 7.50 (dd, 1H), 6.78 (s, 2H), 3.50 (t, 1H),3.43-3.31 (m, 6H), 3.27 (s, 1H), 1.94 (d, 3H), 1.90 (t, 1H), 1.81 (t,1H), 1.74-1.70 (m, 4H). I-N-258 411.1 1.8* ¹H NMR (500 MHz, DMSO) δ 9.79(s, 1H), 9.52 (dd, 1H), 9.37 (s, 1H), 8.96 (d, 1H), 8.43 (d, 1H), 7.51(d, 1H), 6.78 (s, 2H), 3.92-3.87 (m, 2H), 3.72 (d, 1H), 3.60 (d, 1H),3.10 (td, 1H), 2.87 (td, 1H), 2.77 (t, 1H), 2.35-2.23 (m, 2H), 2.13-2.06(m, 1H), 1.61-1.54 (m, 1H). I-N-259 326.1 1.81* ¹H NMR (500 MHz,DMSO-d6) δ 9.99 (s, 1H), 9.52-9.54 (d, 1H), 9.16 (d, 1H), 8.87 (m, 1H),8.81 (s, 1H), 7.90 (d, 1H), 7.08 (d, 1H), 6.74 (s, 2H), 4.22 (d, 3H).I-N-260 439.1 2.4* ¹H NMR (500 MHz, DMSO-d6) δ 2.41 (3H, s), 3.43-3.47(4H, m), 3.53-3.57 (4H, m), 6.80 (2H, brs), 7.51 (1H, d), 8.45 (1H, d),8.87 (1H, d), 9.37 (1H, s), 9.52-9.56 (1H, m), 9.63 (1H, brs), 9.77 (1H,s). I-N-261 433.1 2.29* ¹H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.53(s, 1H), 9.47-9.49 (dd, 1H), 8.86 (d, 1H), 8.27 (s, 1H), 6.79 (s, 2H),3.64-3.66 (m, 7H), 3.05-3.07 (m, 4H). I-N-262 453.2 2.29* ¹H NMR (500MHz, DMSO-d6) δ 9.67 (s, 1H), 9.51 (dd, J = 4.7, 2.6 Hz, 1H), 9.40 (d, J= 1.1 Hz, 1H), 9.19 (dd, J = 2.6, 0.8 Hz, 1H), 8.44 (dd, J = 6.7, 1.1Hz, 1H), 7.53 (d, J = 6.7 Hz, 1H), 6.79 (s, 2H), 3.71-3.60 (m, 2H), 3.51(t, J = 6.7 Hz, 2H), 3.21 (td, J = 12.8, 3.9 Hz, 2H), 3.08-2.94 (m, 2H),2.01 (d, J = 6.9 Hz, 5H), 1.81 (p, J = 6.8 Hz, 2H), 1.42 (dd, J = 12.6,2.2 Hz, 2H). I-N-263 354.1 1.34* ¹H NMR (500 MHz, DMSO) δ 9.74 (s, 1H),9.60 (s, 1H), 9.46 (dd, J = 4.8, 2.5 Hz, 1H), 8.84 (s, 1H), 8.55 (d, J =5.1 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 5.1 Hz, 1H), 6.67(s, 1H), 2.27 (s, 3H). I-N-264 371.0 2.49* run in d6-DMSO I-N-265 438.12.02* ¹H NMR (500 MHz, DMSO-d6) δ 2.02-2.18 (4H, m), 2.37 (3H, s),3.21-3.27 (2H, m), 3.30-3.37 (1H, m), 3.68-3.75 (2H, m), 6.80 (2H, brs),7.58 (1H, d), 8.48 (1H, d), 8.87 (1H, d), 9.33 (1H, s), 9.53-9.56 (1H,m), 9.72 (1H, brs). I-N-266 387.2 2.18* ¹H NMR (500 MHz, DMSO-d6) δ 9.63(s, 1H), 9.52 (dd, J = 4.8, 2.5 Hz, 1H), 9.22 (d, J = 1.1 Hz, 1H), 8.82(d, J = 2.5 Hz, 1H), 8.40 (dd, J = 6.6, 1.1 Hz, 1H), 7.49 (d, J = 6.6Hz, 1H), 6.77 (s, 2H), 3.49 (dtt, J = 11.8, 7.5, 3.6 Hz, 3H), 3.26 (s,3H), 3.26-3.12 (m, 2H), 2.09-1.92 (m, 2H), 1.80-1.61 (m, 2H). I-N-267413.1 2.14* ¹H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.48 (dd, J = 4.8,2.5 Hz, 1H), 9.41 (s, 1H), 8.79 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 5.3Hz, 1H), 7.16 (d, J = 5.3 Hz, 1H), 6.77 (s, 2H), 3.32 (s, 2H), 3.16 (dt,J = 12.0, 3.3 Hz, 2H), 2.68 (td, J = 11.8, 2.4 Hz, 2H), 2.18 (s, 6H),1.79 (dd, J = 13.3, 3.6 Hz, 2H), 1.63 (s, 1H), 1.49-1.41 (m, 2H).I-N-268 424.1 1.93* ¹H NMR (500 MHz, DMSO-d6) δ 2.02-2.13 (2H, m),2.14-2.24 (2H, m), 3.21-3.27 (2H, m), 3.38-3.42 (1H, m), 3.68-3.75 (2H,m), 6.80 (2H, brs), 7.58 (1H, d), 8.48 (1H, d), 8.85 (1H, d), 9.22 (1H,s), 9.33 (1H, s), 9.53-9.55 (1H, m), 9.72 (1H, brs). I-N-269 367.1 1.89*¹H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.50 (dd, J = 4.8, 2.5 Hz,1H), 9.36 (s, 1H), 9.33 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.40 (d, J =2.5 Hz, 1H), 7.73 (d, J = 5.1 Hz, 1H), 6.74 (s, 2H), 2.38 (d, J = 1.0Hz, 3H), 2.04 (d, J = 1.0 Hz, 3H). I-N-270 374.1 2.88* ¹H NMR (500 MHz,DMSO-d6) δ 10.41 (s, 1H), 9.51 (s, 1H), 9.49 (dd, 1H), 8.77 (d, 1H),8.24 (d, 1H), 6.79 (s, 2H), 3.03 (br t, 4H), 1.80-1.76 (m, 4H),1.669-1.65 (m, 2H). I-N-271 475.1 2.21* ¹H NMR (500 MHz, DMSO-d6) δ2.01-2.12 (2H, m), 2.12-2.18 (2H, m), 2.22-2.28 (2H, m), 2.92-3.02 (2H,m), 3.38-3.46 (2H, m), 3.52-3.60 (3H, m), 3.92-3.97 (4H, m), 6.82 (2H,brs), 7.45-7.48 (1H, m), 8.40 (1H, brs), 8.80 (1H, d), 9.45-9.50 (1H,m), 9.53-9.56 (1H, m), 9.83 (1H, s). I-N-272 459.1 2.38* ¹H NMR (500MHz, DMSO-d6) δ 1.83 (2H, m), 2.02 (2H, m), 3.19 (3H, s), 2.30 (4H, m),2.89-2.91 (2H, m), 3.25 (2H, m), 3.70 (2H, m), 6.80 (2H, br s), 8.24(1H, d), 8.71 (1H, d), 9.49 (2H, m) and 10.31 (1H, br s) ppm. I-N-273562.1 2.25* ¹H NMR (500 MHz, DMSO-d6) δ 2.0-2.2 (10H, m), 2.90-3.05 (3H,m), 3.35-3.42 (2H, m), 3.42-3.53 (3H, m), 3.60-3.68 (1H, m), 3.75-3.79(2H, m), 4.30-4.33 (1H, m), 8.28 (1H, d), 8.94 (1H, d), 9.50-9.53 (1H,m), 9.66 (1H, s), 10.23 (1H, brs), 10.43 (1H, s). I-N-274 473.0 2.03* —I-N-275 417.1 1.96* ¹H NMR (500 MHz, Methanol-d4) δ1.03 (s, 1H), 9.52(d, 1H), 9.05 (d, 1H), 8.72 (d, 1H), 8.36 (d, 1H), 3.85-3.91 (m, 4H),3.35-3.40 (masked, 4H), 2.15 (s, 3H). I-N-276 443.0 2.24* — I-N-277443.1 2.1* ¹H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.56 (s, 1H), 9.49(dd, J = 4.8, 2.5 Hz, 1H), 8.86 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.7Hz, 1H), 6.80 (s, 2H), 4.60 (dd, J = 12.1, 2.7 Hz, 1H), 3.75 (d, J = 8.1Hz, 1H), 3.15-3.06 (m, 2H), 3.05-2.89 (m, 3H), 2.33-2.26 (m, 2H), 1.93(dt, J = 13.5, 4.7 Hz, 1H), 1.75 (p, J = 4.1 Hz, 2H), 1.51-1.40 (m, 1H).I-N-278 459.0 1.94* ¹H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.53-9.55(d, 1H), 9.48-9.49 (dd, 1H), 8.88 (d, 1H), 8.29 (d, 1H), 6.80 (s, 2H),4.71-4.76 (m, 4H), 4.17-4.23 (m, 1H), 3.75(m, 2H), 3.741-3.43 (m, 2H),3.05-3.07 (m, 2H). I-N-279 443.1 2.09* ¹H NMR (500 MHz, DMSO) δ 10.39(s, 1H), 9.56 (s, 1H), 9.49 (dd, J = 4.8, 2.5 Hz, 1H), 8.86 (d, J = 2.5Hz, 1H), 8.28 (d, J = 2.7 Hz, 1H), 6.84-6.74 (m, 2H), 4.63-4.56 (m, 1H),3.74 (d, J = 11.3 Hz, 1H), 3.15-3.06 (m, 2H), 3.05-2.89 (m, 3H), 2.29(dd, J = 9.7, 4.8 Hz, 2H), 1.93 (dt, J = 13.5, 4.6 Hz, 1H), 1.75 (dq, J= 10.2, 4.4 Hz, 2H), 1.51-1.40 (m, 1H). I-N-280 443.1 2.1* ¹H NMR (500MHz, DMSO) δ 10.38 (s, 1H), 9.56 (s, 1H), 9.49 (dd, J = 4.8, 2.5 Hz,1H), 8.86 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 6.78 (s, 2H),4.63-4.56 (m, 1H), 3.75 (q, J = 8.5 Hz, 1H), 3.17-3.06 (m, 2H),3.06-2.89 (m, 3H), 2.29 (t, J = 7.3 Hz, 2H), 1.93 (dq, J = 13.4, 4.5,4.0 Hz, 1H), 1.81-1.71 (m, 2H), 1.45 (dtd, J = 14.2, 9.5, 4.7 Hz, 1H).I-N-281 376.0 2.87* ¹H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.53 (dd,J = 4.8, 2.5 Hz, 1H), 9.35 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.41 (s,1H), 3.52-3.45 (m, 4H), 2.12-2.04 (m, 4H). I-N-282 400.0 2.46* ¹H NMR(500 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.52 (dd, J = 4.8, 2.5 Hz, 1H), 9.28(d, J = 1.1 Hz, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.39 (dd, J = 6.6, 1.0Hz, 1H), 7.48 (d, J = 6.5 Hz, 1H), 6.78 (s, 2H), 3.65 (dt, J = 13.2, 3.4Hz, 2H), 3.30 (d, J = 13.4 Hz, 6H), 2.98 (td, J = 12.5, 2.5 Hz, 2H),1.91-1.67 (m, 3H), 1.66-1.46 (m, 2H). I-N-283 353.1 1.75* ¹H NMR (500MHz, DMSO-d6) δ 9.82 (d, J = 0.6 Hz, 1H), 9.58 (s, 1H), 9.42 (dd, J =4.8, 2.5 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H),7.80 (d, J = 1.1 Hz, 1H), 7.50 (dd, J = 5.0, 0.6 Hz, 1H), 7.08 (t, J =1.1 Hz, 1H), 6.70 (s, 2H), 2.01 (d, J = 1.1 Hz, 3H). I-N-284 392.1 2.03*¹H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.48-9.49 (m, 1H), 9.19 (s,1H), 8.78 (d, 1H), 8.36 (s, 1H), 6.80 (s, 2H), 4.45-4.48 (m, 1H),3.78-3.80 (m, 1H), 3.70-3.73 (m, 1H), 3.41-3.45 (m, 1H), 3.35-3.37 (m,1H), 2.10-2.15 (m, 1H), 1.88-1.93 (m, 1H). I-N-285 401.0 2.4* — I-N-286431.1 2.25* — I-N-287 454.0 2.11* — I-N-288 440.3 2.16* — I-N-289 500.02.2* ¹H NMR (500 MHz, DMSO-d6) δ 1.50-1.60 (1H, m), 1.75-1.95 (2H, m),2.01-2.12 (2H, m), 2.70-2.90 (5H, m), 3.00-3.15 (5H, m), 3.20-3.45 (2H,m), 3.85-3.97 (2H, m), 4.40-4.45 (1H, m), 6.85-6.93 (2H, br s), 8.28(1H, d), 8.94 (1H, d), 9.51-9.53 (2H, dd), 9.60-9.70 (1H, s),10.30-10.33 (1H, s). I-N-290 427.0 2.02* ¹H NMR (500 MHz, DMSO-d6) δ9.60 (s, 1H), 9.52-9.54 (dd, 1H), 9.09 (d, 1H), 8.94 (dd, 1H), 8.36-8.38(dd, 1H), 6.77 (s, 2H), 3.74-3.77 (m, 2H), 3.11-3.18 (m, 1H), 2.90-3.05(m, 2H), 2.71 (s, 3H), 2.55 (s, 3H), 1.95-1.98 (m, 1H), 1.77-1.79 (m,2H), 1.46-1.51 (m, 1H). I-G-1 482.3 0.63 ¹H NMR (500 MHz, MeOD) δ 9.52(d, J = 1.2 Hz, 1H), 9.06 (dd, J = 4.3, 2.5 Hz, 1H), 8.88 (dd, J = 2.6,0.5 Hz, 1H), 8.34 (dd, J = 6.6, 1.2 Hz, 1H), 7.56 (d, J = 6.7 Hz, 1H),4.77 (s, 2H), 4.36 (s, 2H), 3.78 (dm, J = 13.0 Hz, 2H), 3.57 (s, 2H),3.22-3.01 (m, 5H), 2.95 (s, 3H), 2.20 (dm, J = 12.2 Hz, 2H), 1.91 (dm,2H). I-G-2 427.2 0.65 ¹H NMR (500 MHz, MeOD) δ 9.60 (s, 1H), 9.02 (dd, J= 2.6, 0.6 Hz, 1H), 9.00 (dd, J = 4.3, 2.5 Hz, 1H), 8.21 (d, J = 5.4 Hz,1H), 7.25 (d, J = 5.4 Hz, 1H), 3.29 (dt, J = 11.6, 2.6 Hz, 2H), 3.20 (s,3H), 3.03 (s, 3H), 2.95 (tt, J = 11.7, 3.8 Hz, 1H), 2.87 (td, J = 12.1,2.3 Hz, 2H), 2.25 (qd, 2H), 1.87 (dm, 2H). I-G-3 516.2 0.77 ¹H NMR (500MHz, MeOD) δ 10.65 (s, 1H), 9.81 (d, J = 1.3 Hz, 1H), 9.21 (dd, J = 2.6,0.8 Hz, 1H), 9.04 (dd, J = 4.3, 2.6 Hz, 1H), 8.30 (s, 1H), 4.57-4.28 (m,2H), 3.75-3.65 (m, 2H), 3.69-3.45 (m, 4H), 3.25-3.07 (m, 4H), 3.03 (dt,J = 12.2, 3.6 Hz, 1H), 3.00 (s, 3H), 2.40-2.23 (m, 2H), 1.91 (dm, J =12.7 Hz, 2H). I-G-4 500.2 0.72 ¹H NMR (500 MHz, MeOD) δ 10.67 (s, 1H),9.69 (d, J = 0.6 Hz, 1H), 9.20 (dd, J = 2.7, 0.6 Hz, 1H), 9.01 (dd, J =4.3, 2.6 Hz, 1H), 8.16 (d, J = 3.0 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H),3.74 (t, J = 5.1 Hz, 2H), 3.72-3.65 (m, 2H), 3.34-3.28 (m, 2H), 3.18(tt, J = 12.0, 2.4 Hz, 2H), 3.06-2.95 (m, 1H), 2.60-2.45 (m, 4H), 2.38(s, 3H), 2.36-2.25 (m, 2H), 1.91-1.79 (m, 2H). I-G-5 516.2 2.34* ¹H NMR(500 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.66 (s, 1H), 9.44 (d, J = 2.2 Hz,1H), 9.03 (d, J = 2.2 Hz, 1H), 8.32-8.24 (m, 1H), 6.85 (s, 2H), 4.47(dd, J = 115.4, 12.9 Hz, 2H), 3.48 (d, J = 10.4 Hz, 2H), 3.40 (t, J =13.5 Hz, 1H), 3.20 (d, J = 10.8 Hz, 2H), 3.10-2.94 (m, 6H), 2.85 (d, J =2.9 Hz, 3H), 2.12 (dd, J = 43.1, 13.1 Hz, 2H), 1.84-1.73 (m, 2H). I-G-6514.2 2.28* ¹H NMR (500 MHz, DMSO-d6) δ 1.7-1.8 (2H, m), 2.1-2.25 (4H,m), 2.85-3.0 (4H, m), 3.05-3.12 (3H, m), 3.2-3.3 (3H, m), 3.4-3.55 (3H,m), 3.6-3.75 (2H, m), 4.05-4.15 (1H, m), 6.8 (2H, brs), 8.28 (1H, d),9.25 (1H, d), 9.5-9.6 (2H, m), 9.7 (1H, d), 10.63-10.66 (1H, m). I-G-7526.2 2.21* ¹H NMR (500 MHz, DMSO-d6, 370 K) δ 10.50 (s, 1H), 9.62 (s,1H), 9.27 (dd, J = 4.7, 2.4 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 6.53 (s,2H), 3.78-3.67 (m, 2H), 3.22 (tm, J = 11.6 Hz, 2H), 3.09 (dm, 2H),3.02-2.83 (m, 8H), 2.29-2.14 (m, 3H), 1.96-1.84 (m, 2H), 1.83-1.64 (m,2H). I-G-8 457.1 2.35* ¹H NMR (500 MHz, DMSO-d6) δ 1.7-1.75 (2H, m),2.05-2.15 (2H, m), 2.2-2.28 (2H, m), 2.4-2.5 (1H, m), 3.03-3.18 (4H, m),3.95 (2H, t), 4.25 (2H, t), 8.28 (1H, d), 9.38 (1H, d), 9.47-9.50 (1H,m), 9.7 (1H, s), 10.65 (1H, s). I-G-9 514.0 2.40* ¹H NMR (500 MHz,DMSO-d6) δ 1.23 (3H, t), 1.75-1.81 (2H, m), 2.05-2.20 (2H, m), 2.97-3.1(5H, m), 3.15-3.25 (4H, m), 3.4-3.57 (3H, m), 4.35-4.4 (1H, m), 4.6-4.65(1H, m), 8.28 (1H, d), 9.18 (1H, d), 9.48-9.56 (2H, m), 9.68 (1H, s),10.65 (1H, s). I-G-10 526.2 2.46* ¹H NMR (500 MHz, DMSO-d6) δ 1.5-1.6(1H, m), 1.70-1.81 (3H, m), 1.90-2.25 (5H, m), 2.90-3.1 (4H, m),3.18-3.37 (4H, m), 3.4-3.5 (1H, m), 3.6-3.9 (3H, m), 3.9-4.0 (1H, m),6.6-6.85 (2H, m), 8.26 (1H, d), 9.1-9.2 (1H, m), 9.47-9.51 (2H, m), 9.68(1H, s), 10.1 (1H, brs), 10.67 (1H, s). I-G-11 514.2 2.30* ¹H NMR (500MHz, DMSO-d6) δ 1.78-1.84 (2H, m), 2.00-2.18 (4H, m), 2.28-2.4 (2H, m),2.45-2.55 (1H, m), 2.70-2.80 (1H, m), 2.80-2.90 (6H, m), 3.05-3.12 (2H,m), 3.12-3.22 (3H, m), 4.35-4.4 (1H, m), 4.6-4.65 (1H, m), 6.78 (2H,brs), 8.28 (1H, d), 9.35 (1H, d), 9.48-9.50 (1H, m), 9.70 (1H, s),9.75-9.85 (1H, m), 10.67-10.69 (1H, m). I-G-12 486.2 1.99* ¹H NMR (500MHz, DMSO-d6) δ 1.75-1.80 (2H, m), 2.08-2.15 (2H, m), 2.92-3.00 (1H, m),3.05-3.25 (8H, m), 3.72-3.78 (2H, m), 3.80-3.85 (2H, m), 6.79 (2H, brs),8.23 (1H, d), 8.72 (2H, brs), 9.15 (1H, d), 9.48 (1H, d), 9.65 (1H, s),10.63 (1H, s). I-G-13 526.1 2.62* ¹H NMR (500 MHz, CDCl3) δ 0.57 (4H, brs), 1.82-1.85 (2H, d), 2.03 (21H, s), 2.33-2.35 (2H, m), 2.60-2.85 (4H,m), 3.13-3.15 (2H, m), 3.24-3.29 (2H, m), 3.70 (4H, br s), 5.84 (2H, s),8.20 (2H, d), 8.48-8.49 (1H, d), 9.34 (1H, d), 9.80 (1H, s), 10.6 (1H,s). I-G-14 498.4 2.13* ¹H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.68(s, 1H), 9.47-9.48 (dd, 1H), 9.35 (dd, 1H), 8.25-8.26 (d, 1H), 6.79 (s,2H), 4.69 (s, 4H), 4.41 (s, 2H), 4.10 (s, 2H), 3.10-3.13 (m, 2H),3.02-3.05 (m, 2H), 2.45-2.50 (m, 2H), 2.04-2.08 (m, 2H), 1.72-1.75 (m,2H). I-G-15 528.2 2.43* — I-G-16 516.3 2.29* ¹H NMR (500 MHz, DMSO-d6) δ1.75-1.95 (3H, m), 2.10-2.25 (2H, m), 2.78-2.85 (5H, m), 2.90-3.00 (1H,m), 3.02-3.15 (5H, m), 3.17-3.26 (2H, m), 3.43-3.52 (2H, m), 8.27-8.29(1H, m), 9.22 (1H, s), 9.27 (1H, d), 9.48-9.53 (1H, m), 9.68-9.71 (1H,m), 10.64-10.68 (1H, s). I-G-18 526.2 2.30* ¹H NMR (500 MHz, DMSO-d6) δ1.75-1.90 (2H, m), 2.10-2.22 (2H, m), 2.70-2.82 (1H, m), 2.85-2.93 (4H,m), 2.96-3.12 (3H, m), 3.12-3.22 (2H, m), 3.23-3.35 (2H, m), 3.40-3.55(2H, m), 3.59-3.75 (2H, m), 3.78-3.90 (2H, m), 6.75-6.90 (1H, m), 8.28(1H, d), 9.37 (1H, d), 9.48-9.53 (1H, m), 9.69 (1H, s), 9.74-9.88 (1H,m), 10.66 (1H, s). I-G-19 473.2 2.78* — I-G-20 514.2 2.14* — I-G-21487.1 2.31* ¹H NMR (500 MHz, DMSO-d6) δ 1.68-1.75 (2H, m), 2.01-2.14(2H, m), 2.35-2.40 (1H, masked), 3.05-3.15 (4H, m), 3.24 (3H, s),3.71-3.74 (1H, m), 4.05-4.12 (2H, m), 4.22-4.24 (1H, m), 4.41-4.44 (1H,m), 6.70-7.00 (2H, br s), 8.29 (1H, d), 9.36 (1H, dd), 9.47-9.49 (1H,dd), 9.67 (1H, s), 10.62 (1H, s). I-G-22 500.2 2.23* — I-G-23 486.12.04* — I-G-24 500.2 2.14* — I-G-25 525.2 2.35* ¹H NMR (500 MHz,DMSO-d6) δ 2.22-2.25 (2H, m), 2.35-2.50 (6H, masked), 2.87 (3H, s),3.05-3.25 (4H, m), 3.30-3.35 (2H, m), 4.70-4.80 (2H, m), 6.77-6.92 (2H,br s), 8.32 (1H, d), 8.69 (1H, dd), 9.51-9.53 (1H, dd), 9.64 (1H, s),9.80-9.95 (1H, br s), 10.37 (1H, s). I-G-26 502.0 2.07* ¹H NMR (500 MHz,DMSO-d6) δ 1.77-1.83 (4H, m), 2.10-2.18 (2H, m), 2.36-2.42 (1H, m),2.78-2.80 (6H, m), 3.05-3.09 (6H, m), 3.18-3.22 (2H, m), 6.80 (2H, brs), 8.16-8.18 (1H, m), 8.27 (1H, d), 9.34-9.36 (2H, m), 9.49-9.50 (1H,d), 9.67 (1H, s), 10.62 (1H, s). I-G-27 514.2 2.19* — I-G-28 512.2 2.2*— I-G-29 445.0 2.37* ¹H NMR (500 MHz, DMSO-d6) δ 1.74-1.77 (2H, m),2.05-2.15 (2H, m), 2.88-2.91 (4H, m), 3.03-3.05 (2H, m), 3.11 (3H, s),3.15-3.22 (2H, m), 6.79 (1H, s), 8.25 (1H, d), 9.34 (1H, dd), 9.47-9.49(1H, dd), 9.68 (1H, s), 10.66 (1H, s). I-G-30 489.2 2.12* — I-G-31 502.12.33* — I-G-32 542.3 2.14* ¹H NMR (500 MHz, methanol-d4) δ 1.87 (2H, m),2.27-2.33 (2H, m), 2.55 (4H, m), 2.97-3.03 (1H, m), 3.18 (2H, m),3.70-3.85 (4H, m), 4.67-4.70 (2H, m), 4.75-4.78 (2H, m), 8.16 (1H, d),9.00 (1H, dd), 9.17 (1H, dd), 9.68 (1H, s), 10.65 (1H, s). I-G-33 432.12.07* — I-G-34 486.1 2.07* — I-G-35 540.2 2.74* — I-G-36 487.0 2.34* —I-G-37 473.1 2.04* — I-G-38 526.2 2.39* — I-G-40 489.2 2.45* — I-G-41473.1 1.97* ¹H NMR (500 MHz, DMSO-d6) δ 1.87 (2H, m), 2.25 (2H, m), 2.61(1H, m), 3.84 (1H, m), 4.10 (1H, m), 4.28 (1H, m), 4.55 (1H, m), 4.62(1H, m), 4.80 (3H, masked), 8.32 (1H, d), 9.05 (1H, dd), 9.24 (1H, d),9.69 (1H, s), 10.56 (1H, s). I-G-42 500.2 2.11* — I-G-43 526.0 2.43* —I-G-44 512.0 2.18* — I-G-45 500.0 2.14* ¹H NMR (500 MHz, DMSO-d6) δ1.14-1.17 (3H, m), 1.83-1.86 (2H, m), 2.22-2.34 (2H, m), 2.37-2.45 (1H,m), 2.75-2.88 (3H, m), 2.92-3.12 (2H, m), 3.11-3.20 (3H, m), 3.28-3.335(1H, masked), 4.01-4.08 (1H, m), 4.46-4.54 (1H, m), 8.14 (1H, s),8.99-9.00 (1H, m), 9.19 (1H, m), 9.67 (1H, s). I-G-46 512.1 2.15* —I-G-47 514.2 2.37* — I-G-48 504.1 2.15* ¹H NMR (500 MHz, DMSO-d6) δ10.69 (s, 1H), 9.81 (s, 1H), 9.46 (dd, J = 4.7, 2.5 Hz, 1H), 9.35 (s,1H), 8.24 (s, 1H), 6.79 (s, 2H), 3.58-3.44 (m, 6H), 2.95-2.84 (m, 3H),2.68 (dt, J = 22.8, 4.7 Hz, 4H), 2.40 (s, 1H), 2.21-2.11 (m, 2H),1.77-1.70 (m, 2H). I-G-49 512.1 2.29* — I-G-50 514.2 2.38* — I-G-51512.1 2.03* — I-G-52 526.2 2.46* ¹'H NMR (500 MHz, DMSO-d6) δ 1.72-1.76(1H, m), 1.83-1.85 (1H, m), 1.92-1.98 (3H, m), 2.05-2.12 (2H, m),2.15-2.25 (1H, m), 2.80 (3H, s), 2.89 (1H, m), 3.05-3.25 (7H, m),3.45-3.47 (2H, m), 4.78-4.80 (2H, m), 6.82 (2H, br s), 8.27 (1H, d),9.27 (1H, d), 9.49-9.51 (1H, dd), 9.68 (1H, s), 10.65 (1H, s). I-G-53512.1 2.18* — I-G-54 514.2 2.29* ¹H NMR (500 MHz, DMSO-d6) δ 10.35 (s,1H), 9.81 (s, 1H), 9.53 (s, 1H), 9.51 (dd, J = 4.8, 2.5 Hz, 1H), 8.64(d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.7 Hz, 1H), 6.81 (s, 2H), 4.50 (d, J= 14.0 Hz, 2H), 3.46 (d, J = 11.7 Hz, 2H), 3.28-3.10 (m, 4H), 3.10-2.89(m, 4H), 2.83 (s, 3H), 2.30 (ddd, J = 13.1, 8.9, 3.4 Hz, 2H), 1.86-1.67(m, 2H), 1.40 (s, 3H). I-G-55 496.2 2.17* ¹H NMR (500 MHz, DMSO-d6) δ10.57 (s, 1H), 9.67 (s, 1H), 9.45 (dd, J = 4.8, 2.5 Hz, 1H), 9.25 (s,1H), 8.04 (s, 1H), 6.78 (s, 2H), 3.64 (d, J = 37.4 Hz, 4H), 3.16-3.07(m, 1H), 3.01-2.87 (m, 3H), 2.70-2.56 (m, 5H), 2.41 (s, 6H), 2.23-2.09(m, 2H), 1.77-1.67 (m, 2H), 1.19 (t, J = 7.3 Hz, 1H). I-G-56 482.2 1.94*¹H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.73 (s, 1H), 9.50 (dd, J =4.8, 2.6 Hz, 1H), 9.38-9.30 (m, 1H), 8.08 (d, J = 0.8 Hz, 1H), 6.83 (s,2H), 3.61 (dt, J = 26.1, 5.2 Hz, 4H), 2.97 (tt, J = 11.8, 3.6 Hz, 3H),2.85 (dt, J = 23.8, 5.0 Hz, 4H), 2.46 (s, 5H), 2.28-2.15 (m, 2H), 1.77(dd, J = 12.2, 3.4 Hz, 2H). I-G-57 540.0 2.69* — I-G-58 540.0 2.57* —I-G-59 554.0 2.45* — I-G-60 568.0 2.58* — I-G-61 500.2 2.14* — I-G-62498.0 2.17* — I-G-63 487.0 2.17* — I-G-64 554.0 2.75* — I-G-65 512.02.41* ¹H NMR (500 MHz, DMSO-d6) δ 0.64-0.78 (2H, m), 1.75-1.88 (2H, m),2.05-2.24 (3H, m), 2.34-2.35 (3H, m), 2.50-2.55 (1H, masked), 2.61-2.63(1H, m), 2.71-2.74 (1H, m), 3.05-3.20 (6H, m), 4.07-4.09 (1H, m), 6.79(2H, s), 8.26 (1H, d), 9.45 (1H, d), 9.48 (1H, dd), 9.69 (1H, s), 10.68(1H, s). I-G-66 542.1 2.41* ¹H NMR (500 MHz, DMSO) δ 10.71 (d, J = 19.7Hz, 1H), 9.82 (d, J = 12.7 Hz, 1H), 9.47 (dt, J = 4.7, 2.9 Hz, 1H), 9.31(s, 1H), 8.24 (d, J = 1.0 Hz, 1H), 6.80 (s, 2H), 4.54-4.23 (m, 1H), 3.73(dt, J = 31.9, 5.7 Hz, 2H), 3.59-3.50 (m, 2H), 2.96-2.79 (m, 9H), 2.20(dd, J = 26.6, 13.3 Hz, 2H), 1.87 (d, J = 13.8 Hz, 3H), 1.76 (d, J =12.7 Hz, 2H), 1.65 (tt, J = 10.1, 4.8 Hz, 1H). I-G-67 474.4 2.42* —I-G-68 542.0 2.42* ¹H NMR (500 MHz, DMSO-d6) δ 1.05-1.25 (2H, m),1.71-1.78 (2H, m), 1.95-1.98 (2H, m), 2.05-2.25 (3H, m), 2.340-2.45 (2H,masked), 2.60 (1H, m), 2.95-3.10 (4H, m), 3.15-3.22 (2H, m), 3.35-3.40(1H, m), 4.04-4.08 (2H, m), 4.15-4.27 (3H, m), 4.52-4.55 (1H, m), 6.80(2H, br s), 8.27 (1H, d), 9.22 (1H, dd), 9.48-9.50 (1H, dd), 9.67 (1H,s), 9.90-10.00 (1H, s), 10.62 (1H, s). I-G-69 528.1 2.30* ¹H NMR (500MHz, DMSO) δ 10.54 (s, 1H), 9.75 (s, 1H), 9.33-9.28 (m, 2H), 8.22 (s,1H), 6.58 (s, 2H), 3.55 (t, J = 11.6 Hz, 2H), 2.26-2.11 (m, 4H),3.01-2.93 (m, 3H), 2.80 (s, 2H), 2.47 (d, J = 11.4 Hz, 2H), 1.96 (s,1H), 1.77 (d, J = 13.6 Hz, 3H), 2.39-2.34 (m, 1H), 2.68-2.60 (m, 2H).I-G-70 512.0 2.11* ¹H NMR (500 MHz, DMSO-d6) δ 1.70-1.80 (2H, m),1.81-1.97 (2H, m), 2.05-2.15 (2H, m), 2.40-2.50 (2H, masked), 2.55-2.60(1H, m), 2.78-2.83 (2H, m), 2.85-3.05 (2H, m), 3.10-3.20 (2H, m),3.72-3.74 (1H, m), 3.96-3.98 (1H, m), 4.51 (1H, m), 5.05 (1H, m), 6.79(2H, s), 8.25 (1H, m), 9.31 (1H, d), 9.35 (1H, d), 9.45 (1H, m), 9.67(1H, d), 10.60 (1H, d). I-G-71 512.0 2.11* ¹H NMR (500 MHz, DMSO-d6) δ1.70-1.80 (2H, m), 1.81-1.97 (2H, m), 2.05-2.15 (2H, m), 2.40-2.50 (1H,masked), 2.55-2.60 (1H, m), 2.78-2.83 (2H, m), 2.85-3.05 (2H, m),3.72-3.74 (1H, m), 3.96-3.98 (1H, m), 4.51 (1H, m), 5.05 (1H, m), 6.79(2H, s), 8.25 (1H, m), 9.31 (1H, d), 9.35 (1H, d), 9.45 (1H, m), 9.67(1H, d), 10.60 (1H, d). I-G-72 499.1 2.13* ¹H NMR (500 MHz, DMSO-d6) δ10.63 (s, 1H), 9.68 (s, 1H), 9.47-9.48 (dd, 1H), 9.35 (dd, 1H),8.25-8.26 (d, 1H), 6.79 (s, 2H), 4.69 (s, 4H), 4.41 (s, 2H), 4.10 (s,2H), 3.10-3.13 (m, 2H), 3.02-3.05 (m, 2H), 2.45-2.50 (m, 2H), 2.04-2.08(m, 2H), 1.72-1.75 (m, 2H). I-G-73 493.0 2.63* ¹H NMR (500 MHz, DMSO-d6)δ 10.62 (s, 1H), 9.67 (s, 1H), 9.48-9.50 (dd, 1H), 9.27 (dd, 1H), 8.28(d, 1H), 6.80 (be s, 2H), 4.76 (m, 2H), 4.38 (m, 2H), 3.14 (m, 2H),3.08-3.11 (m, 2H), 2.55-2.60 (m, 1H), 2.03-2.15 (m, 2H), 1.82-1.84 (m,2H). I-G-74 475.1 2.42* — I-G-75 501.0 2.5* — I-G-76 482.1 2.22* ¹H NMR(500 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.67 (s, 1H), 9.48-9.50 (dd, 1H),9.30 (dd, 1H), 8.28 (d, 1H), 6.80 (br s, 2H), 4.55-4.56 (m, 1H),4.46-4.49 (m, 1H), 4.21-4.25 (m, 1H), 4.07-4.11 (m, 1H), 3.81-3.85 (m,1H), 3.05-3.17 (m, 4H), 2.50-2.55 (masked, 1H), 2.03-2.09 (m, 2H),1.75-1.81 (m, 2H). I-G-77 439.1 2.02* ¹H NMR (500 MHz, DMSO-d6) δ 9.86(s, 1H), 9.53 (dd, J = 4.7, 2.5 Hz, 1H), 9.45 (d, J = 1.0 Hz, 1H), 9.02(dd, J = 2.6, 0.6 Hz, 1H), 8.44 (dd, J = 6.5, 1.1 Hz, 1H), 7.55 (d, J =6.5 Hz, 1H), 6.80 (s, 2H), 4.21 (t, J = 7.6 Hz, 2H), 3.89 (t, J = 7.7Hz, 2H), 3.58 (dt, J = 12.3, 3.2 Hz, 2H), 3.02 (td, J = 12.5, 2.5 Hz,2H), 2.59-2.52 (m, 1H), 2.26-2.16 (m, 2H), 2.06-1.94 (m, 2H), 1.80-1.72(m, 2H). I-G-78 469.1 1.99* — I-G-79 483.0 2.12* ¹H NMR (500 MHz,DMSO-d6) δ 9.83 (s, 1H), 9.53 (dd, J = 4.8, 2.5 Hz, 1H), 9.45 (d, J =1.0 Hz, 1H), 9.00 (dd, J = 2.5, 0.6 Hz, 1H), 8.46 (dd, J = 6.5, 1.1 Hz,1H), 7.58 (d, J = 6.5 Hz, 1H), 6.80 (s, 2H), 4.17-4.11 (m, 1H), 4.00(dd, J = 8.8, 1.2 Hz, 1H), 3.80 (d, J = 9.9 Hz, 1H), 3.68 (dd, J = 10.0,1.2 Hz, 1H), 3.60 (dt, J = 12.5, 3.3 Hz, 2H), 3.18 (s, 3H), 3.06-2.98(m, 2H), 2.57 (ddt, J = 11.7, 8.3, 4.2 Hz, 1H), 2.06-1.94 (m, 2H),1.83-1.75 (m, 2H), 1.42 (s, 3H). I-G-80 475.1 2.24* — I-G-81 464.1 1.92*¹H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.54 (dd, J = 4.7, 2.5 Hz,1H), 9.44 (d, J = 1.0 Hz, 1H), 8.96 (dd, J = 2.5, 0.5 Hz, 1H), 8.46 (dd,J = 6.5, 1.1 Hz, 1H), 7.57 (d, J = 6.5 Hz, 1H), 6.80 (s, 2H), 4.55-4.41(m, 2H), 4.19 (t, J = 9.4 Hz, 1H), 4.05 (dd, J = 9.6, 6.1 Hz, 1H), 3.81(tt, J = 9.1, 6.1 Hz, 1H), 3.64-3.56 (m, 2H), 3.02 (td, J = 12.4, 2.6Hz, 2H), 2.61-2.52 (m, 1H), 2.04-1.90 (m, 2H), 1.80 (dd, J = 30.8, 12.9Hz, 2H). I-G-82 457.1 2.04* — I-G-83 453.1 2.21* ¹H NMR (500 MHz,DMSO-d6) δ 9.86 (d, J = 1.5 Hz, 1H), 9.53 (ddd, J = 4.9, 2.6, 1.0 Hz,1H), 9.46 (dd, J = 2.5, 1.1 Hz, 1H), 9.06-9.01 (m, 1H), 8.46 (ddd, J =6.4, 2.5, 1.1 Hz, 1H), 7.57 (dd, J = 6.6, 1.7 Hz, 1H), 6.80 (s, 2H),3.62 (dt, J = 12.8, 3.2 Hz, 2H), 3.53 (t, J = 6.8 Hz, 2H), 3.33 (t, J =6.9 Hz, 2H), 3.05 (td, J = 12.5, 2.4 Hz, 2H), 2.77 (tt, J = 11.5, 3.9Hz, 1H), 2.05 (qd, J = 12.7, 3.9 Hz, 2H), 1.96-1.86 (m, 2H), 1.85-1.75(m, 4H). I-G-84 495.1 1.94* ¹H NMR (500 MHz, DMSO-d6) δ 9.84 (q, J = 1.7Hz, 1H), 9.54 (ddd, J = 4.7, 2.6, 2.0 Hz, 1H), 9.45 (q, J = 1.6 Hz, 1H),9.06-8.96 (m, 1H), 8.46 (ddd, J = 6.5, 2.6, 1.2 Hz, 1H), 7.61-7.52 (m,1H), 6.80 (s, 2H), 4.55 (d, J = 6.1 Hz, 1H), 4.52-4.34 (m, 2H), 3.82 (s,1H), 3.71-3.24 (m, 6H), 3.11-2.99 (m, 2H), 2.76 (dddd, J = 21.0, 17.3,12.3, 6.9 Hz, 1H), 2.21 (t, J = 6.9 Hz, 1H), 2.13-1.97 (m, 3H), 1.82(td, J = 13.2, 6.7 Hz, 2H). I-G-85 469.1 1.97* ¹H NMR (500 MHz, DMSO-d6)δ 9.79 (s, 1H), 9.54 (dd, J = 4.8, 2.5 Hz, 1H), 9.41 (d, J = 1.1 Hz,1H), 8.97-8.90 (m, 1H), 8.45 (dd, J = 6.6, 1.1 Hz, 1H), 7.56 (d, J = 6.6Hz, 1H), 6.80 (s, 2H), 3.68-3.54 (m, 8H), 3.50 (t, J = 4.5 Hz, 2H),3.16-2.94 (m, 3H), 2.07-1.96 (m, 2H), 1.81-1.71 (m, 2H). I-G-86 535.02.12* — I-G-87 542.0 2.33* ¹H NMR (500 MHz, DMSO-d6) δ 11.28 (1H, brs),10.56 (0.4H, s), 10.52 (0.6H, s), 9.66 0.4H, s), 9.63 (0.6H, s), 9.44(1H, d), 9.22 (0.4H, d), 8.99 (0.6H, d), 8.38 (1H, dd), 4.72 (0.6H,brs), 4.58 (0.4H, brs), 3.96-3.99 (2H, m), 3.20-3.40 (8H, m), 3.11-3.12(2H, m), 1.98-2.15 (7H, m), 1.77-1.80 (2H, m). I-G-88 481.1 1.86* —I-G-89 517.1 1.81* ¹H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.64 (s,1H), 9.47 (dd, J = 4.8, 2.5 Hz, 1H), 9.06 (dd, J = 2.5, 0.6 Hz, 1H),8.23 (d, J = 5.2 Hz, 1H), 7.21 (dd, J = 5.2, 0.6 Hz, 1H), 6.77 (s, 2H),4.59-4.52 (m, 1H), 4.43 (dd, J = 9.5, 4.9 Hz, 1H), 4.31 (tt, J = 8.4,5.0 Hz, 1H), 4.20 (dd, J = 10.4, 8.5 Hz, 1H), 4.14-4.07 (m, 1H),3.14-3.08 (m, 2H), 3.07 (s, 3H), 2.75 (tdd, J = 11.9, 6.5, 2.4 Hz, 2H),2.48 (dt, J = 11.8, 4.0 Hz, 1H), 2.14-2.00 (m, 2H), 1.76 (dt, J = 12.5,3.0 Hz, 2H). I-G-90 481.1 1.96* ¹H NMR (500 MHz, DMSO-d6) δ 9.83 (s,1H), 9.52 (dd, J = 4.7, 2.5 Hz, 1H), 9.44 (d, J = 1.1 Hz, 1H), 8.98 (d,J = 2.5 Hz, 1H), 8.44 (dd, J = 6.5, 1.1 Hz, 1H), 7.55 (d, J = 6.5 Hz,1H), 6.80 (s, 2H), 4.49-4.38 (m, 3H), 4.33 (dd, J = 10.0, 1.7 Hz, 1H),4.14 (dd, J = 11.3, 1.7 Hz, 1H), 3.96 (dd, J = 11.2, 1.7 Hz, 1H),3.61-3.54 (m, 2H), 3.01 (tt, J = 12.5, 3.2 Hz, 2H), 2.84 (t, J = 7.5 Hz,2H), 2.59-2.52 (m, 1H), 1.97 (qq, J = 12.5, 4.8, 4.3 Hz, 2H), 1.81-1.73(m, 2H). I-G-91 483.1 2.18* ¹H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H),9.53 (dd, J = 4.8, 2.5 Hz, 1H), 9.45 (d, J = 0.9 Hz, 1H), 9.04-8.98 (m,1H), 8.43 (dd, J = 6.4, 1.0 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), 6.80 (s,2H), 4.40 (ddd, J = 9.1, 6.5, 1.3 Hz, 1H), 4.30 (tt, J = 6.5, 4.0 Hz,1H), 4.11-3.99 (m, 2H), 3.70-3.66 (m, 1H), 3.56 (d, J = 12.5 Hz, 2H),3.43 (qd, J = 7.0, 2.3 Hz, 2H), 3.05-2.96 (m, 2H), 2.61-2.52 (m, 1H),1.99 (qt, J = 12.6, 3.5 Hz, 2H), 1.79 (q, J = 12.8, 11.8 Hz, 2H), 1.14(t, J = 7.0 Hz, 3H). I-G-92 556.0 2.37* ¹H NMR (500 MHz, DMSO-d6) δ10.62 (s, 1H), 9.67 (s, 1H), 9.49-9.50 (dd, 1H), 9.19 (d, 1H), 8.28 (d,1H), 6.81 (s, 2H), 4.30-4.90 (m, 7H), 2.98-3.21 (m, 10H), 2.15-2.20 (m,2H), 1.78-1.80 (m, 2H), 1.58 (m, 3H). I-G-93 483.1 2.07* ¹H NMR (500MHz, DMSO-d6) δ 9.88-9.83 (m, 1H), 9.53 (dd, J = 4.8, 2.5 Hz, 1H), 9.45(dd, J = 2.2, 1.1 Hz, 1H), 9.02 (t, J = 2.5 Hz, 1H), 8.44 (dd, J = 6.4,1.1 Hz, 1H), 7.56 (dd, J = 6.5, 1.6 Hz, 1H), 6.79 (s, 2H), 3.99 (dtt, J= 37.7, 4.6, 2.3 Hz, 1H), 3.71-3.43 (m, 5H), 3.41-3.27 (m, 1H), 3.25 (d,J = 11.0 Hz, 3H), 3.05 (tq, J = 12.4, 2.5 Hz, 2H), 2.78 (qt, J = 11.6,3.9 Hz, 1H), 2.12-1.76 (m, 6H). I-G-94 483.0 2.07* ¹H NMR (500 MHz,DMSO-d6) δ 9.87 (d, J = 1.5 Hz, 1H), 9.54 (dd, J = 4.7, 2.5 Hz, 1H),9.46 (dd, J = 2.2, 1.0 Hz, 1H), 9.02 (t, J = 2.7 Hz, 1H), 8.44 (dd, J =6.4, 1.0 Hz, 1H), 7.55 (dd, J = 6.5, 1.6 Hz, 1H), 6.80 (s, 2H), 3.99(dtt, J = 37.8, 4.5, 2.3 Hz, 1H), 3.71-3.43 (m, 5H), 3.40-3.27 (m, 1H),3.25 (d, J = 10.9 Hz, 3H), 3.03 (dddd, J = 12.9, 8.3, 3.9, 2.3 Hz, 2H),2.77 (qt, J = 11.0, 3.7 Hz, 1H), 2.12-1.86 (m, 4H), 1.80 (dt, J = 13.6,6.9 Hz, 2H). I-G-95 516.1 1.79* ¹H NMR (500 MHz, DMSO-d6) δ 12.48 (s,1H), 10.64 (s, 1H), 9.68 (s, 1H), 9.50 (dd, 1H), 9.17 (dd, 1H), 8.28 (d,1H), 6.81 (s, 2H), 4.54 (d, 1H), 4.31 (d, 1H), 3.79-3.69 (m, 5H), 3.53(s, 3H), 3.36-3.30 (m, 1H), 3.24-3.18 (m, 2H), 3.09-3.01 (m, 3H),2.21-2.07 (m, 2H), 1.79 (br d, 2H). I-G-96 555.2 2.13* ¹H NMR (500 MHz,DMSO-d6) δ 10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd, J = 4.8, 2.5 Hz, 1H),9.29-9.18 (m, 1H), 8.26 (d, J = 2.4 Hz, 1H), 6.79 (s, 2H), 3.65-3.50 (m,4H), 3.38 (s, 1H), 3.19 (t, J = 11.7 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H),2.95 (t, J = 11.7 Hz, 1H), 2.82 (d, J = 31.4 Hz, 3H), 2.65 (p, J = 1.9Hz, 1H), 2.55 (s, 1H), 2.37 (p, J = 1.9 Hz, 1H), 2.30-2.19 (m, 7H),2.18-2.06 (m, 2H), 1.78-1.69 (m, 2H), 1.25 (s, 2H). I-G-98 501.0 2.44*¹H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.67 (s, 1H), 9.47-9.49 (dd,1H), 9.38 (dd, 1H), 8.28 (d, 1H), 6.80 (s, 2H), 4.27-4.30 (m, 1H),3.93-3.97 (m, 2H), 3.61-3.64 (m, 1H), 3.49-3.51 (m, 2H), 3.30 (s, 3H),3.15-3.16 (m, 2H), 3.10-3.11 (m, 2H), 2.80-2.83 (m, 1H), 2.35-2.40(masked, 1H), 2.00-2.10 (m, 2H), 1.70-1.80 (m, 2H). I-G-99 501.1 2.45* —Retention times measured using HPLC Method B, described in theExperimental Methods and Materials section, above., are designated by(*). For all other compounds, the retention time was measured using theHPLC Method A.

Preparation O-1 (S)-tert-butyl3-((3-aminopyridin-4-yl)oxy)piperidine-1-carboxylate

Step 1: tert-butyl(3S)-3-[(3-nitro-4-pyridyl)oxy]piperidine-1-carboxylate

Sodium hydride (492.0 mg, 12.30 mmol) was added to a solution oftert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (2.095 g, 10.41 mmol)in THF (20 mL) and the reaction stirred at 0° C. for 15 minutes. Asuspension of 4-chloro-3-nitro-pyridine (1.5 g, 9.461 mmol) in THF (10mL) was added and the reaction allowed to warm slowly to ambienttemperature over 2 hours. The reaction was quenched with water and themixture was partitioned between EtOAc and brine. The combined organicextract was washed with brine, dried (MgSO₄), filtered and concentratedin vacuo. The residue was purified by column chromatography (ISCOCompanion, 80 g column, eluting with 0 to 100% EtOAc/Petroleum Ether) togive tert-butyl (3S)-3-[(3-nitro-4-pyridyl)oxy]piperidine-1-carboxylateas a pale yellow solid (2.65 g, 87% Yield, 93% ee). MS (ES+) 324.1.

Step 2: (S)-tert-butyl3-((3-aminopyridin-4-yl)oxy)piperidine-1-carboxylate

Pd on C, (10%, wet, Degussa) (1 g, 0.9397 mmol) was added to a stirredsolution of tert-butyl(3S)-3-[(3-nitro-4-pyridyl)oxy]piperidine-1-carboxylate (2.65 g, 8.196mmol) in EtOAc (30 mL)/EtOH (15 mL). The reaction was placed under anatmosphere of hydrogen and stirred at ambient temperature for 16 hours.The catalyst was removed by filtration through a pad of celite and thefiltrate concentrated in vacuo to give the sub-title compound as anoff-white solid (2.46 g, >100% Yield). MS (2ES+) 587.3.

The following aminopyridines were prepared using Preparation O-1:

Miscellaneous Preparation of Aminopyridines

Preparation O-24-((6-((dimethylamino)methyl)pyridin-3-yl)oxy)pyridin-3-amine

Step 1: 6-((dimethylamino)methyl)pyridin-3-ol

6-(aminomethyl)pyridin-3-ol (150 mg, 1.208 mmol), formic acid (1 mL,26.51 mmol), formaldehyde (1 mL, 36.30 mmol) was heated at 100° C.overnight. The mixture was concentrated in vacuo to yield6-((dimethylamino)methyl)pyridin-3-ol that was used in next step withoutfurther purification.

Step 2:N,N-dimethyl-1-(5-((3-nitropyridin-4-yl)oxy)pyridin-2-yl)methanamine

To a solution of 6-((dimethylamino)methyl)pyridin-3-ol in DMF (5 mL) wasadded, K₂CO₃ (834.8 mg, 6.040 mmol) and the mixture was stirred at RTfor 10 min before 4-chloro-3-nitro-pyridine (191.5 mg, 1.208 mmol) wasadded. The mixture was stirred at RT for 60 h. The reaction mixture waspartitioned between EtOAc and NH₄Cl aq satd. Combined organic extractwas washed with brine, dried (MgSO₄) and concentrated in vacuo yieldingan oil that purified by SCX column, yieldingN,N-dimethyl-1-(5-((3-nitropyridin-4-yl)oxy)pyridin-2-yl)methanamine asa colourless oil. MS (ES+) 275.1.

Step 3: 4-((6-((dimethylamino)methyl)pyridin-3-yl)oxy)pyridin-3-amine

N,N-dimethyl-1-(5-((3-nitropyridin-4-yl)oxy)pyridin-2-yl)methanamine(150 mg, 0.5469 mmol), Pd/C (10%) (58.20 mg, 0.5469 mmol) in MeOH (15mL) was stirred overnight at RT under hydrogen (balloon). The catalystwas filtered off and the filtrate was concentrated in vacuo to yield thetitle product as a clear oil. MS (ES+) 245.2.

The following aminopyridine synthesized using Step 2 and Step 3 ofPreparation O-2:

Preparation O-3(1s,4s)-4-((3-aminopyridin-4-yl)oxy)-N,N-dimethylcyclohexanecarboxamide

Step 1: 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylic acid

Methyl 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylate (250.0 mg,0.8920 mmol) (prepared according to methods similar to the one depictedin Step 1 of preparation O-1) in THF (2.748 mL), Water (2.748 mL) andMeOH (1.5 mL) solution was stirred at RT and treated with Lithiumhydroxide monohydrate (Water (1)) (224.6 mg, 5.352 mmol). The mixturewas stirred at RT overnight, then was concentrated under reducedpressure to remove the organics. The aqueous solution was cooled in anice bath then acidified with HCl (5.352 mL of 1 M, 5.352 mmol) to pH4-5. Ethyl acetate was then added and the layers separated. Aqueouslayer was extracted further with ethyl acetate (2×5 mL) and the combinedorganic layers were dried over MgSO₄ and concentrated in vacuo to leavethe 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylic acid as a yellowoil. Used in the next step without further purification. MS (ES+) 267.0.

Step 2: N,N-dimethyl-4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxamide

TBTU (630.0 mg, 1.962 mmol) and dimethylamine (1.784 mL of 2 M, 3.568mmol) were added to a solution of4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylic acid (475 mg, 1.784mmol) and DIPEA (253.6 mg, 341.8 μL, 1.962 mmol) in THF (9.500 mL) andthe resulting solution was stirred at RT overnight. The reaction mixturewas partitioned between EtOAc and water, and the combined organicextracts were dried over MgSO₄ and concentrated in vacuo. The residuewas purified by column chromatography on silica eluting with 0-100%EtOAc/petroleum ether using the ISCO column companion system (12 gcolumn). Clean fractions were combined and concentrated in vacuo toyield N,N-dimethyl-4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxamide as apale yellow oil. (180 mg, 34%). MS (ES+) 294.3.

Step 3:(1s,4s)-4-((3-aminopyridin-4-yl)oxy)-N,N-dimethylcyclohexanecarboxamide

Pd on C, (10%, wet, Degussa) (65.31 mg, 0.06137 mmol) was added to asolution ofN,N-dimethyl-4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxamide (180 mg,0.6137 mmol) in methanol (6.300 mL) and the reaction mixture was stirredunder a hydrogen atmosphere overnight. The catalyst was filtered off andthe filtrate was concentrated in vacuo to leave the title product as ayellow oil. (160 mg, 99%), MS (ES+) 264.3.

The following aminopyridine was synthesized according to methods similarto the one depicted in Preparation O-3:

-   ((1s,4s)-4-((3-aminopyridin-4-yl)oxy)cyclohexyl)(4-methylpiperazin-1-yl)methanone

Preparation O-4 4-((3-aminopyridin-4-yl)oxy)tetrahydro-2H-thiopyran1-oxide and 4-((3-aminopyridin-4-yl)oxy)tetrahydro-2H-thiopyran1,1-dioxide

An amount of mCPBA (513.0 mg, 2.081 mmol) was added to a solution of3-nitro-4-((tetrahydro-2H-thiopyran-4-yl)oxy)pyridine (preparedaccording to methods similar to the one depicted in Preparation O-1)(400 mg, 1.665 mmol) in DCM (10 mL) at RT. The mixture was stirred at RTovernight before 5 mL of an aqueous saturated solution of NaHCO₃ and 5mL of an aqueous saturated solution of Na₂S₂O₃ was added. The mixturewas stirred at RT for 30 min, partitioned between DCM and water.Combined organic extract was washed with brine, dried (MgSO₄) andconcentrated in vacuo yielding an oil that was dissolved in MeOH (15mL). Pd/C 10% (177.2 mg, 1.665 mmol) was added and the mixture washydrogenated (H² balloon) overnight. The catalyst was filtered off andthe filtrate was concentrated in vacuo to yield a 1/1 mixture of“sulfoxide and sulfone aminopyridine” intermediates that was used innext step without further purification.

MS (ES+) 227.1 (sulfoxide); and

MS (ES+) 243.1 (sulfone).

Preparation O-5 5-fluoro-4-((1-methylpiperidin-4-yl)oxy)pyridin-3-amine

Step 1: 2-bromo-5-fluoro-4-((1-methylpiperidin-4-yl)oxy)-3-nitropyridine

NaH (86.67 mg, 2.167 mmol) was added portionwise to a solution of1-methylpiperidin-4-ol (192.0 mg, 1.667 mmol) in THF (5.000 mL) at 0° C.and the resulting solution stirred for 15 min and then2,4-dibromo-5-fluoro-3-nitro-pyridine (500 mg, 1.667 mmol) in THF (5.000mL) was added and the reaction mixture stirred at RT overnight. Thereaction mixture was partitioned between water (10 mL) and ethyl acetate(10 mL). Combined organic extracts was dried over MgSO₄ and concentratedin vacuo. The residue was purified by column chromatograph on silicaeluting with ethyl acetate/petroleum ether (24 g column, 0-100% EtOAc)using the ISCO column companion system. Product fractions were combinedand concentrated in vacuo to leave the product as a yellow oil thatsolidified on standing. (125 mg). MS (ES+) 334.0 336.0.

Step 2: 5-fluoro-4-((1-methylpiperidin-4-yl)oxy)pyridin-3-amine

A solution of2-bromo-5-fluoro-4-[(1-methyl-4-piperidyl)oxy]-3-nitro-pyridine (96 mg,0.2873 mmol), ZnBr₂ (12.94 mg, 3.080 μL, 0.05746 mmol) and Pd on C, wet,Degussa (31 mg) in methanol (5 mL) was flushed with hydrogen andevacuated (3×) and then stirred under a hydrogen atmosphere overnight.The catalyst was filtered off through a celite pad and washed withmethanol and ethyl acetate mixtures and the filtrate was concentrated invacuo to leave a pale yellow oil that was used in next step withoutfurther purification. MS (ES+) 226.1.

The following aminopyridine was prepared using Step 1 and Step 2 ofPreparation O-5:

-   5-fluoro-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)pyridin-3-amine:

Preparation O-6 tert-butyl(5-amino-4-methoxypyridin-2-yl)(methyl)carbamate

Step 1: tert-butyl (5-iodo-4-methoxypyridin-2-yl)(methyl)carbamate

Sodium hydride (37.70 mg, 0.9425 mmol) was added to a stirred suspensionof tert-butyl N-(5-iodo-4-methoxy-2-pyridyl)carbamate (300 mg, 0.8568mmol) in DMF (3 mL) and the reaction was stirred at 0° C. for 15minutes. MeI (145.9 mg, 63.99 μL, 1.028 mmol) was added and the reactionallowed to warm to ambient temperature over 1 hour. The mixture wasquenched by the addition of water, diluted with EtOAc and the layersseparated. The organic layer washed with saturated aqueous NaHCO₃ (×1),brine (×2), dried (MgSO₄) filtered and concentrated in vacuo. Theresidue was purified by column chromatography (ISCO Companion, 40 gcolumn, eluting with 0 to 30% EtOAc/Petroleum Ether, loaded in DCM) togive tert-butyl (5-iodo-4-methoxypyridin-2-yl)(methyl)carbamate as acolourless oil (269 mg, 86% Yield). MS (ES+−t-Bu) 309.4.

Step 2: tert-butyl(5-((diphenylmethylene)amino)-4-methoxypyridin-2-yl)(methyl)carbamate

Pd₂(dba)₃ (33.70 mg, 0.03680 mmol) and Xantphos (42.58 mg, 0.07359 mmol)were added to a sealed tube containing tert-butylN-(5-iodo-4-methoxy-2-pyridyl)-N-methyl-carbamate (268 mg, 0.7359 mmol),diphenylmethanimine (173.4 mg, 160.6 μL, 0.9567 mmol) and Cs₂CO₃ (719.4mg, 2.208 mmol) in dioxane (2.5 mL). The reaction was placed under anatmosphere of nitrogen and heated at 100° C. for 4 hours. At RT, thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo. The residue was purified by column chromatography(ISCO Companion, 40 g column, eluting with 0 to 30% EtOAc/PetroleumEther, loaded in DCM) to give tert-butyl(5-((diphenylmethylene)amino)-4-methoxypyridin-2-yl)(methyl)carbamate asa yellow solid (213 mg, 69% Yield). MS (ES+) 418.2.

Step 3: tert-butyl (5-amino-4-methoxypyridin-2-yl)(methyl)carbamate

HCl (100 μL of 2 M, 0.2000 mmol) was added to a stirred solution oftert-butylN-[5-(benzhydrylideneamino)-4-methoxy-2-pyridyl]-N-methyl-carbamate (212mg, 0.5078 mmol) in THF (2 mL) and the reaction was stirred at ambienttemperature for 18 hours. The resultant precipitate was isolated byfiltration and the filtrate stirred at ambient temperature for a further6 hours. The reaction was diluted with 1M HCl and extracted with Et₂O(×3). The aqueous layer was made basic by the addition of saturatedaqueous NaHCO₃ and extracted with DCM (×3). The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo to givetert-butyl (5-amino-4-methoxypyridin-2-yl)(methyl)carbamate as a red oil(98.2 mg, 76% Yield). MS (ES+) 254.1.

The following compounds were synthesized using a procedure similar toExample 1 or Example 3a:

-   (S)-2-amino-6-fluoro-N-(4-((1-methylpyrrolidin-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-1);-   (R,S)-2-amino-6-(cyanomethyl)-N-(4-(piperidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-2);-   2-amino-N-(4-((6-((dimethylamino)methyl)pyridin-3-yl)oxy)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-3);-   2-amino-6-fluoro-N-(4-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-4);-   (R)-2-amino-6-fluoro-N-(4-(quinuclidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-5);-   (R,S)-2-amino-6-fluoro-N-(4-(quinuclidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-6);-   2-amino-6-fluoro-N-(4-(pyridin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-7);-   4-((3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)oxy)cyclohexanecarboxylic    acid (Compound I-O-8);-   (S)-2-amino-6-fluoro-N-(4-((1-(oxetan-3-yl)piperidin-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-9);-   (S)-2-amino-6-fluoro-N-(4-(quinuclidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-10);-   2-amino-6-fluoro-N-(4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-11);-   2-amino-6-fluoro-N-(4-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-12);-   (1r,4r)-methyl    4-((3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)oxy)cyclohexanecarboxylate    (Compound I-O-13);-   2-amino-N-(4-ethoxypyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-14);-   (R,S)-2-amino-6-fluoro-N-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-15);-   (S)-2-amino-N-(4-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)oxy)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-16);-   2-amino-N-(4-(((1s,4s)-4-(dimethylcarbamoyl)cyclohexyl)oxy)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-17);-   (1s,4s)-methyl    4-((3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)oxy)cyclohexanecarboxylate    (Compound I-O-18);-   2-amino-6-fluoro-N-(4-(((1s,4s)-4-(4-methylpiperazine-1-carbonyl)cyclohexyl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-19);-   2-amino-6-(1-cyanopropyl)-N-(4-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-20);-   2-amino-6-(1-cyanoethyl)-N-(4-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-21);-   (R,S)-2-amino-6-(cyanomethyl)-N-(4-(quinuclidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-22);-   2-amino-6-(cyanomethyl)-N-(4-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-23);-   2-amino-6-(cyanomethyl)-N-(4-(2-(dimethylamino)ethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-24);-   2-amino-6-(cyanomethyl)-N-(4-phenoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-25);-   2-amino-6-(cyanomethyl)-N-(4-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-26);-   2-amino-N-(6-chloro-4-methoxypyridin-3-yl)-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-27);-   2-amino-6-(cyanomethyl)-N-(4-ethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-28);-   2-amino-6-(cyanomethyl)-N-(4-(2-methoxyethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-29);-   2-amino-6-(cyanomethyl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-30);-   (R)-2-amino-6-(cyanomethyl)-N-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-31);-   2-amino-6-(cyanomethyl)-N-(4-(cyclopropylmethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-32);-   2-amino-6-(cyanomethyl)-N-(4-(2-hydroxyethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-33);-   2-amino-6-(cyanomethyl)-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-34);-   2-amino-6-(cyanomethyl)-N-(4-isopropoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-35);-   2-amino-6-(cyanomethyl)-N-(4-cyclobutoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-36);-   (R,S)-2-amino-6-(cyanomethyl)-N-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-37);-   2-amino-6-(cyanomethyl)-N-(4-(oxetan-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-38);-   2-amino-6-(cyanomethyl)-N-(4-(cyclohexyloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-39);-   2-amino-6-(cyanomethyl)-N-(4-(3-hydroxypropoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-40);-   2-amino-6-(cyanomethyl)-N-(4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-41);-   (S)-2-amino-6-(cyanomethyl)-N-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-42);-   2-amino-6-(cyanomethyl)-N-(4-(cyclopentyloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-43);-   2-amino-6-fluoro-N-(4-((1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-44);-   2-amino-N-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-45);-   2-amino-6-chloro-N-(5-chloro-4-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-46);-   2-amino-6-chloro-N-(4-(2-(2-(dimethylamino)ethoxy)ethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-47);-   2-amino-6-chloro-N-(4-(2-(dimethylamino)ethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-48);-   (R)-2-amino-6-chloro-N-(4-((1-methylpyrrolidin-2-yl)methoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-49);-   (S)-2-amino-6-chloro-N-(4-((1-methylpyrrolidin-2-yl)methoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-50);-   2-amino-6-chloro-N-(4-((1-methylpiperidin-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-51);-   2-amino-6-chloro-N-(4-(3-(dimethylamino)propoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-52);-   2-amino-6-chloro-N-(4-(3-hydroxypropoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-53);-   (R)-2-amino-6-chloro-N-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-54);-   2-amino-6-chloro-N-(4-(2-methoxyethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-55);-   2-amino-6-chloro-N-(4-ethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-56);-   2-amino-6-chloro-N-(4-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-57);-   (S)-2-amino-6-chloro-N-(4-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-58);-   2-amino-6-chloro-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-59);-   2-amino-6-chloro-N-(4-(2-morpholinoethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-60);-   2-amino-6-chloro-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-61);-   2-amino-6-chloro-N-(4-(quinuclidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-62);-   (R)-2-amino-6-chloro-N-(4-((1-methylpyrrolidin-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-63);-   2-amino-6-chloro-N-(4-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-64);-   2-amino-6-chloro-N-(4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-65);-   2-amino-6-chloro-N-(4-(2-hydroxyethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-66);-   (S)-2-amino-6-chloro-N-(4-((1-(2-methoxyethyl)piperidin-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-67);-   2-amino-6-chloro-N-(6-chloro-4-(2-(dimethylamino)ethoxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-68);-   (S)-2-amino-6-chloro-N-(4-((1-methylpyrrolidin-3-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-69);-   2-amino-6-chloro-N-(4-(pyridin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-70);-   2-amino-6-chloro-N-(4-(2-(dimethylamino)ethoxy)-6-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-71);-   2-amino-N-(4-(tert-butoxy)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-88);-   2-amino-6-fluoro-N-(5-fluoro-4-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-89);-   2-amino-6-fluoro-N-(5-fluoro-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-91); and-   2-amino-6-fluoro-N-(4-(oxetan-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-92).

The following compounds were prepared using a procedure similar toExample 2:

-   N-(4-(2-azaspiro[3.3]heptan-6-yloxy)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-72);-   2-amino-N-(4-(azetidin-3-yloxy)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-73);-   (S)-2-amino-6-chloro-N-(4-(piperidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-74);-   2-amino-6-chloro-N-(4-(piperidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-75);-   (S)-2-amino-6-chloro-N-(4-(pyrrolidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-76);-   (R)-2-amino-6-chloro-N-(4-(pyrrolidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-77);-   N-(4-((4s,6r)-1-azaspiro[3.3]heptan-6-yloxy)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-78);-   N-(4-((4r,6s)-1-azaspiro[3.3]heptan-6-yloxy)pyridin-3-yl)-2-amino-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-79);-   2-amino-6-chloro-N-(4-(piperidin-4-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-80);-   (R)-2-amino-6-chloro-N-(4-(piperidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-81);-   2-amino-N-(4-(azetidin-3-yloxy)pyridin-3-yl)-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-82);-   2-amino-N-(4-(2-aminoethoxy)pyridin-3-yl)-6-(cyanomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-83);-   2-amino-6-(cyanomethyl)-N-(4-(piperidin-4-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-84);-   (S)-2-amino-6-fluoro-N-(4-(piperidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-85);-   (S)-2-amino-6-(cyanomethyl)-N-(4-(pyrrolidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-86);-   (R)-2-amino-6-(cyanomethyl)-N-(4-(pyrrolidin-3-yloxy)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-87); and-   2-amino-6-fluoro-N-(4-methoxy-6-(methylamino)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-O-90).

Compound Analytical Data Cmpd LCMS LCMS No. ES+ (Rt min) HNMR I-O-1372.2 0.60 ¹H NMR (500 MHz, DMSO-d6) δ 10.4-10.6 (s, 1H), 10.05-10.15(s, 1H), 9.64 (s, 1H), 9.54-9.56 (dd, 1H), 8.91 (s, 1H), 8.47-8.48 (d,1H), 7.52 (s, 1H), 6.79 (s, 2H), 5.50-5.60 (m, 1H), 4.10-4.15 (s < 1H),3.85-3.95 (s, 2H), 3.20-3.60 (m, 3H), 2.93 (s, 3H), 2.80-2.90 (s, 1H).I-O-2 393.1 0.56 ¹H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.55 (s,1H), 9.06 (dt, J = 2.0, 0.7 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.17 (d,J = 5.5 Hz, 1H), 7.20 (d, J = 5.6 Hz, 1H), 6.75 (s, 2H), 4.63-4.53 (m,1H), 4.15 (d, J = 0.7 Hz, 2H), 3.20-3.11 (m, 1H), 2.85-2.75 (m, 2H),2.69-2.61 (m, 1H), 2.17-2.05 (m, 1H), 1.86-1.70 (m, 2H), 1.59-1.44 (m,1H). I-O-3 423.0 0.62 ¹H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.71(s, 1H), 9.50 (dd, J = 4.7, 2.5 Hz, 1H), 8.77 (dd, J = 2.9, 0.6 Hz, 1H),8.73-8.66 (m, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.91 (dd, J = 8.5, 2.9 Hz,1H), 7.69 (dd, J = 8.6, 0.7 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 6.77 (s,2H), 4.50 (s, 2H), 2.84 (s, 6H). I-O-4 303.1 0.60 ¹H NMR (500 MHz,DMSO-d6) δ 4.03 (2H, s), 6.71 (2H, s), 7.15-7.16 (1H, dd), 8.22-8.23(1H, s), 8.87 (1H, d), 9.44 91H, s), 9.45-9.46 (1H, m), 9.96 (1H, s).I-O-5 398.0 0.61 ¹H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.97 (s,1H), 9.68 (s, 1H), 9.55 (dd, J = 4.7, 2.5 Hz, 1H), 8.83-8.79 (m, 1H),8.50 (d, J = 6.0 Hz, 1H), 7.54 (d, J = 6.0 Hz, 1H), 6.82 (s, 2H), 5.30(d, J = 4.2 Hz, 1H), 3.98 (ddd, J = 14.0, 8.3, 2.2 Hz, 1H), 3.50-3.24(m, 5H), 2.68-2.63 (m, 1H), 2.28 (s, 1H), 2.10-2.01 (m, 1H), 1.95 (d, J= 7.2 Hz, 2H). I-O-6 398.2 0.64 — I-O-7 366.1 0.63 ¹H NMR (500 MHz,DMSO-d6) δ 6.80-6.90 (2H, s), 7.23-7.24 (1H, d), 7.62-7.65 (1H, dd),7.87-7.89 (1H, m), 8.43-8.44 (1H, d), 8.61-8.63 (1H, d), 8.72-8.76 (1H,m), 9.50 (1H, d), 8.78 (1H, (1H, s), 10.48 (1H, s) I-O-8 415.3 0.43 ¹HNMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.34 (s, 1H), 9.62 (d, J = 0.9Hz, 1H), 9.53 (dd, J = 4.8, 2.5 Hz, 1H), 8.92 (d, J = 2.5 Hz, 1H), 8.50(d, J = 6.3 Hz, 1H), 7.74 (d, J = 6.3 Hz, 1H), 6.76 (s, 2H), 6.51 (s,1H), 4.90 (s, 1H), 2.22 (dd, J = 12.4, 4.0 Hz, 2H), 2.15-2.01 (m, 2H),1.81-1.53 (m, 4H). I-O-9 428.3 0.63 ¹H NMR (500 MHz, DMSO-d6) δ 10.19(s, 1H), 9.68 (s, 1H), 9.55 (dd, J = 4.8, 2.5 Hz, 1H), 8.82 (d, J = 2.4Hz, 1H), 8.57 (d, J = 6.5 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 6.80 (s,2H), 5.16 (s, 1H), 4.68-4.65 (m, 5H), 4.57 (s, 1H), 4.15 (s, 1H), 3.30(s, 1H), 2.96 (s, 1H), 2.20 (s, 2H), 1.92 (s, 2H). I-O-10 398.0 0.61 ¹HNMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.54 (s, 1H), 9.48 (dd, J = 4.8,2.5 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.07(d, J = 5.5 Hz, 1H), 6.76 (s, 2H), 4.72 (dt, J = 7.3, 3.1 Hz, 1H), 3.38(ddd, J = 14.3, 7.9, 2.1 Hz, 1H), 2.92-2.82 (m, 1H), 2.82-2.64 (m, 3H),2.22 (q, J = 3.2 Hz, 1H), 2.01 (ddt, J = 13.0, 9.8, 4.0 Hz, 1H),1.75-1.66 (m, 1H), 1.66-1.55 (m, 1H), 1.51-1.42 (m, 1H). I-O-11 428.20.59 ¹H NMR (500 MHz, DMSO-d6) δ 2.2-2.36 (4H, m), 3.25 masked signal,4.39 (1H, m), 4.73-4.78 (4H, m), 5.18 (1H, m), 6.81 (2H, br s), 7.71(1H, m), 8.55 (1H, m), 8.78 (1H, m), 9.56 (1H, m), 9.66 (1H, s) and10.18 (1H, br s) ppm I-O-12 386.1 0.59 — I-O-13 429.2 0.78 ¹H NMR (500MHz, DMSO-d6) δ 1.40-1.76 (4H, m), 2.07 (2H, m), 2.21 (2H, m), 2.63 (1H,m), 3.65 (3H, s), 4.91 (1H, m), 6.76 (2H, br s), 7.73 (1H, m), 8.50 (1H,m), 8.92 (1H, s), 9.52 (1H, m), 9.62 (1H, m) and 10.34 (1H, s) ppmI-O-14 317.1 0.60 — I-O-15 359.1 1.86* — I-O-16 395.0 0.55 ¹H NMR (500MHz, DMSO-d6) δ 10.03 (s, 1H), 9.67 (s, 1H), 9.57-9.43 (m, 1H), 8.76 (d,J = 2.5 Hz, 1H), 8.52 (dd, J = 6.1, 2.5 Hz, 1H), 7.79 (d, J = 1.9 Hz,1H), 7.69-7.59 (m, 2H), 6.77 (s, 2H), 6.09 (d, J = 5.7 Hz, 1H), 4.82(dd, J = 13.3, 5.3 Hz, 1H), 4.62 (dd, J = 13.4, 1.1 Hz, 1H), 3.94 (dd, J= 18.2, 6.2 Hz, 1H), 3.53 (d, J = 18.2 Hz, 1H). I-O-17 442.2 0.69 ¹H NMR(500 MHz, DMSO-d6) δ 1.67 (2H, m), 1.85-2.00 (4H, m), 2.12 (2H, m), 2.84(4H, m), 3.09 (3H, s), 5.22 (1H, m), 6.80 (2H, br s), 7.75 (1H, m), 8.56(1H, m), 9.11 (1H, m), 9.52 (1H, m), 9.69 (1H, s) and 10.09 (1H, s) ppmI-O-18 429.2 0.76 ¹H NMR (500 MHz, DMSO-d6) δ 1.75-1.84 (4H, m),1.91-2.03 (4H, m), 2.57 masked signal, 3.58 (3H, s), 4.92 (1H, s), 6.54(1H, s), 6.78 (2H, br s), 7.26 (1H, m), 8.21 (1H, m), 8.68 (1H, m), 9.51(2H, m) and 9.81 (1H, s) ppm I-O-19 497.3 0.66 ¹H NMR (500 MHz, DMSO-d6)δ 1.68 (2H, m), 1.85-1.98 (4H, m), 2.12 (2H, m), 2.84 (3H, s), 2.91 (1H,m), 4.42 masked signal, 5.24 (1H, m), 6.81 (2H, br s), 7.72 (1H, m),8.57 (1H, m), 9.03 (1H, m), 9.53 (1H, m), 9.70 (1H, s) and 10.05 (1H, s)ppm I-O-20 352.1 0.69 ¹H NMR (500 MHz, Methanol-d4) δ 1.2 (3H, t),1.2-2.0 (2H, m), 3.8 (1H, t), 4.45 (3H, s), 7.7 (1H, d), 8.4-8.6 (3H,m), 8.7 (1H, s), 8.9 (1H, s), 9.7 (1H, s), I-O-21 338.1 1.97* ¹H NMR(500 MHz, DMSO-d6) δ 1.7 (3H, d), 4.3 (3H, s), 4.55 (1H, q), 6.68-6.8(2H, m), 7.2 (0.5H, d), 7.5 (0.5H, d), 7.7 (1H, d), 8.15 (1H, d), 8.8(1H, s), 9.2 (1H, s), 9.7 (1H, s), 10.5 (1H, s). I-O-22 419.0 0.63 ¹HNMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 10.07 (d, J = 2.7 Hz, 1H), 9.70(s, 1H), 9.13 (dd, J = 1.6, 0.9 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.54(d, J = 6.4 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 6.81 (s, 2H), 5.33 (d, J= 5.4 Hz, 1H), 4.13 (s, 2H), 4.03-3.93 (m, 1H), 3.48 (d, J = 13.8 Hz,1H), 3.39 (m, 3H), 3.31-3.22 (m, 1H), 2.65 (m, 1H), 2.44 (m, 1H),2.14-1.90 (m, 3H). I-O-23 407.2 0.58 ¹H NMR (500 MHz, DMSO-d6) δ 10.05(s, 1H), 9.55 (s, 1H), 9.06 (dt, J = 1.9, 0.8 Hz, 1H), 8.59 (d, J = 2.0Hz, 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 6.74 (s,2H), 4.68 (dq, J = 8.5, 4.6, 4.2 Hz, 1H), 4.20-4.10 (m, 2H), 2.81-2.66(m, 2H), 2.35-2.24 (m, 2H), 2.21 (s, 3H), 2.12-2.00 (m, 2H), 1.89-1.76(m, 2H). I-O-24 381.1 0.57 ¹H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H),9.60 (s, 1H), 9.12 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.53(d, J = 6.1 Hz, 1H), 7.58 (d, J = 5.7 Hz, 1H), 6.79 (s, 2H), 4.80 (d, J= 4.6 Hz, 2H), 4.14 (s, 2H), 3.77-3.70 (m, 2H), 2.94 (s, 6H). I-O-25386.1 0.74 ¹H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.76 (d, J = 0.8Hz, 1H), 9.08 (dd, J = 1.9, 0.8 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.42(dd, J = 6.3, 0.8 Hz, 1H), 7.67-7.54 (m, 2H), 7.49-7.37 (m, 3H), 7.12(d, J = 6.3 Hz, 1H), 6.79 (s, 2H), 4.07 (s, 2H). I-O-26 324.1 0.56 ¹HNMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.62 (s, 1H), 9.09 (d, J = 2.0Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 6.7 Hz, 1H), 7.67 (d, J= 6.5 Hz, 1H), 6.76 (s, 2H), 4.27 (s, 3H), 4.14 (s, 2H). I-O-27 358.00.68 ¹H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.27 (s, 1H), 9.05 (d, J= 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 7.29 (s, 1H), 6.71 (s, 2H),4.12 (s, 2H), 4.08 (s, 3H). I-O-28 338.1 0.62 ¹H NMR (500 MHz, DMSO-d6)δ 10.51 (s, 1H), 9.63 (s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.65 (d, J =2.0 Hz, 1H), 8.57 (d, J = 6.4 Hz, 1H), 7.64 (d, J = 6.5 Hz, 1H), 6.77(s, 2H), 4.51 (q, J = 7.0 Hz, 2H), 4.14 (s, 2H), 1.63 (t, J = 7.0 Hz,3H). I-O-29 368.2 0.57 ¹H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.64(d, J = 1.0 Hz, 1H), 9.10 (dt, J = 1.5, 0.7 Hz, 1H), 8.65 (d, J = 2.0Hz, 1H), 8.57 (dd, J = 6.4, 1.0 Hz, 1H), 7.68 (d, J = 6.4 Hz, 1H), 6.77(s, 2H), 4.72-4.53 (m, 2H), 4.22-4.11 (m, 2H), 4.02-3.86 (m, 2H), 3.42(s, 3H). I-O-30 394.2 0.60 ¹H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H),9.68 (d, J = 1.0 Hz, 1H), 9.11 (dt, J = 1.6, 0.7 Hz, 1H), 8.63 (d, J =2.0 Hz, 1H), 8.58 (dd, J = 6.6, 1.1 Hz, 1H), 7.83 (d, J = 6.7 Hz, 1H),6.78 (s, 2H), 5.23 (tt, J = 7.9, 3.9 Hz, 1H), 4.15 (s, 2H), 4.02 (ddd, J= 11.4, 5.9, 3.9 Hz, 2H), 3.66 (ddd, J = 11.5, 8.3, 3.1 Hz, 2H),2.23-2.10 (m, 2H), 1.88 (dtd, J = 12.2, 8.1, 3.8 Hz, 2H). I-O-31 380.10.57 ¹H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.63 (d, J = 1.0 Hz,1H), 9.08 (dt, J = 1.6, 0.8 Hz, 1H), 8.60-8.53 (m, 2H), 7.68 (d, J = 6.5Hz, 1H), 6.75 (s, 2H), 5.56 (ddd, J = 5.7, 3.7, 1.8 Hz, 1H), 4.16 (d, J= 0.8 Hz, 2H), 4.13-3.98 (m, 3H), 3.93 (td, J = 8.4, 4.3 Hz, 1H),2.50-2.40 (m, 1H), 2.29-2.18 (m, 1H). I-O-32 364.1 0.69 ¹H NMR (500 MHz,DMSO-d6) δ 10.52 (s, 1H), 9.65 (d, J = 1.0 Hz, 1H), 9.11 (dd, J = 1.9,0.8 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.59-8.48 (m, 1H), 7.60 (d, J =6.5 Hz, 1H), 6.77 (s, 2H), 4.34 (d, J = 7.2 Hz, 2H), 4.14 (s, 2H), 1.50(pt, J = 7.5, 4.7 Hz, 1H), 0.86-0.74 (m, 2H), 0.58-0.46 (m, 2H). I-O-33354.1 0.49 ¹H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.63 (d, J = 0.9Hz, 1H), 9.10 (dd, J = 1.9, 0.8 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.55(d, J = 6.4 Hz, 1H), 7.67 (d, J = 6.4 Hz, 1H), 6.76 (s, 2H), 5.07 (s,1H), 4.50 (t, J = 4.8 Hz, 2H), 4.15 (s, 2H), 4.00 (t, J = 4.7 Hz, 2H).I-O-34 392.1 0.65 ¹H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.72 (d, J= 0.7 Hz, 1H), 9.09 (dt, J = 2.0, 0.7 Hz, 1H), 8.58 (dd, J = 6.2, 0.8Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 6.3 Hz, 1H), 6.77 (s,2H), 5.27 (q, J = 8.4 Hz, 2H), 4.22-4.14 (m, 2H). I-O-35 352.2 0.67 ¹HNMR (500 MHz, DMSO-d6) δ 10.69-10.33 (m, 1H), 9.64 (d, J = 5.6 Hz, 1H),9.23-9.02 (m, 1H), 8.80-8.64 (m, 1H), 8.55 (t, J = 6.5 Hz, 1H), 7.72 (t,J = 5.7 Hz, 1H), 6.76 (s, 2H), 5.19 (hept, J = 6.6 Hz, 1H), 4.29-4.03(m, 2H), 1.67-1.44 (m, 6H). I-O-36 364.1 0.71 ¹H NMR (500 MHz, DMSO-d6)δ 10.48 (s, 1H), 9.63 (d, J = 0.9 Hz, 1H), 9.11 (dt, J = 1.6, 0.7 Hz,1H), 8.69 (d, J = 2.0 Hz, 1H), 8.51 (dd, J = 6.4, 1.0 Hz, 1H), 7.46 (d,J = 6.4 Hz, 1H), 6.77 (s, 2H), 5.29-5.13 (m, 1H), 4.14 (s, 2H),2.73-2.59 (m, 2H), 2.40-2.27 (m, 2H), 2.03-1.91 (m, 1H), 1.80 (dtt, J =10.9, 9.8, 8.3 Hz, 1H). I-O-37 380.2 0.57 ¹H NMR (500 MHz, DMSO-d6) δ10.44 (s, 1H), 9.64 (d, J = 0.9 Hz, 1H), 9.10 (dd, J = 1.9, 0.8 Hz, 1H),8.60 (d, J = 2.0 Hz, 1H), 8.58-8.52 (m, 1H), 7.66 (d, J = 6.4 Hz, 1H),6.77 (s, 2H), 5.57 (ddd, J = 5.6, 3.5, 1.7 Hz, 1H), 4.16 (d, J = 0.9 Hz,2H), 4.13-4.00 (m, 3H), 3.93 (td, J = 8.4, 4.3 Hz, 1H), 2.49-2.40 (m,1H), 2.32-2.19 (m, 1H). I-O-38 366.0 0.54 ¹H NMR (500 MHz, DMSO-d6) δ10.49 (s, 1H), 9.67 (d, J = 0.8 Hz, 1H), 9.11 (dt, J = 1.9, 0.7 Hz, 1H),8.74 (d, J = 2.0 Hz, 1H), 8.51 (dd, J = 6.3, 0.9 Hz, 1H), 7.32 (d, J =6.3 Hz, 1H), 6.77 (s, 2H), 5.75 (tt, J = 5.8, 4.4 Hz, 1H), 5.14 (ddd, J= 7.8, 5.9, 1.1 Hz, 2H), 4.80 (ddd, J = 7.8, 4.4, 1.0 Hz, 2H), 4.16-4.11(m, 2H). I-O-39 392.2 0.79 ¹H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H),9.67 (d, J = 1.0 Hz, 1H), 9.12 (dt, J = 2.0, 0.7 Hz, 1H), 8.61 (d, J =2.0 Hz, 1H), 8.55 (dd, J = 6.6, 1.1 Hz, 1H), 7.77 (d, J = 6.6 Hz, 1H),6.78 (s, 2H), 5.03 (tt, J = 8.0, 3.6 Hz, 1H), 4.20-4.12 (m, 2H),2.15-2.01 (m, 2H), 1.96-1.83 (m, 2H), 1.83-1.69 (m, 2H), 1.66-1.38 (m,4H). I-O-40 368.1 0.52 ¹H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.64(d, J = 1.0 Hz, 1H), 9.09 (dd, J = 1.9, 0.9 Hz, 1H), 8.69-8.47 (m, 2H),7.68 (d, J = 6.5 Hz, 1H), 6.77 (s, 2H), 4.52 (t, J = 5.8 Hz, 2H), 4.15(d, J = 0.8 Hz, 2H), 3.81 (q, J = 7.0, 6.5 Hz, 2H), 2.14 (p, J = 6.0 Hz,2H). I-O-41 394.1 0.62 ¹H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.69(d, J = 1.0 Hz, 1H), 9.10 (dt, J = 1.6, 0.7 Hz, 1H), 8.64 (d, J = 2.0Hz, 1H), 8.55 (dd, J = 6.5, 1.1 Hz, 1H), 7.76 (d, J = 6.6 Hz, 1H), 6.78(s, 2H), 5.03 (h, J = 3.7, 3.2 Hz, 1H), 4.16 (d, J = 0.7 Hz, 2H),3.97-3.85 (m, 2H), 3.83-3.74 (m, 1H), 3.69 (ddd, J = 11.3, 8.1, 3.1 Hz,1H), 2.16 (tt, J = 9.2, 4.7 Hz, 1H), 2.11-1.92 (m, 2H), 1.73-1.59 (m,1H). I-O-42 380.1 0.57 ¹H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.63(d, J = 0.9 Hz, 1H), 9.09 (dd, J = 2.0, 0.8 Hz, 1H), 8.59-8.55 (m, 2H),7.68 (d, J = 6.5 Hz, 1H), 6.75 (s, 2H), 5.57 (ddd, J = 5.9, 3.8, 1.7 Hz,1H), 4.16 (d, J = 0.9 Hz, 2H), 4.13-3.99 (m, 3H), 3.93 (td, J = 8.4, 4.3Hz, 1H), 2.50-2.41 (m, 1H), 2.27-2.21 (m, 1H). I-O-43 378.1 0.74 ¹H NMR(500 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.64 (d, J = 1.0 Hz, 1H), 9.11 (dt,J = 1.9, 0.7 Hz, 1H), 8.63-8.49 (m, 2H), 7.68 (d, J = 6.6 Hz, 1H), 6.78(s, 2H), 5.39 (dq, J = 5.8, 3.7, 2.9 Hz, 1H), 4.20-4.12 (m, 2H),2.20-2.07 (m, 2H), 2.07-1.95 (m, 2H), 1.96-1.84 (m, 2H), 1.83-1.66 (m,2H). I-O-44 405.0 0.5 ¹H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.69 (d,J = 1.0 Hz, 1H), 9.54 (dd, J = 4.7, 2.5 Hz, 1H), 8.77-8.69 (m, 1H), 8.58(dd, J = 6.5, 1.1 Hz, 1H), 7.77 (d, J = 6.6 Hz, 1H), 6.82 (s, 2H),5.34-5.26 (m, 1H), 3.10 (td, J = 13.7, 12.2, 3.0 Hz, 2H), 3.01-2.90 (m,2H), 2.55 (m, 2H), 2.14 (dd, J = 15.1, 4.3 Hz, 2H). I-O-45 421.0 0.56 ¹HNMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.68 (d, J = 0.9 Hz, 1H), 9.55(dd, J = 4.7, 2.5 Hz, 1H), 8.83 (dd, J = 2.5, 0.7 Hz, 1H), 8.58 (dd, J =6.5, 1.0 Hz, 1H), 7.76 (d, J = 6.6 Hz, 1H), 6.82 (s, 2H), 5.34-5.27 (m,1H), 3.50 (ddd, J = 14.4, 10.8, 3.7 Hz, 2H), 3.39-3.32 (m, 2H),2.50-2.34 (m, 4H). I-O-46 436.1 0.8 ¹H NMR (500 MHz, Methanol-d4) δ 2.10(6H, m), 2.27 (3H, s), 2.90 (2H, m), 4.75 (1H, m), 8.28 (1H, s), 8.75(1H, d), 9.02 (1H, m) and 9.61 (1H, s) ppm I-O-47 420.1 0.65 ¹H NMR (500MHz, DMSO-d6) δ 10.03 (s, 1H), 9.48 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H),8.67 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 5.5 Hz, 1H), 7.17 (d, J = 5.5 Hz,1H), 6.77 (s, 2H), 4.37-4.31 (m, 2H), 3.95-3.89 (m, 2H), 3.60 (t, J =6.0 Hz, 2H), 2.36 (t, J = 6.0 Hz, 2H), 2.07 (s, 6H). I-O-48 376.1 0.66¹H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.48 (s, 1H), 9.42 (d, J = 2.3Hz, 1H), 8.62-8.56 (m, 1H), 8.20 (d, J = 5.6 Hz, 1H), 7.19 (d, J = 5.6Hz, 1H), 6.78 (s, 2H), 4.30 (t, J = 5.6 Hz, 2H), 2.84 (t, J = 5.6 Hz,2H), 2.26 (s, 6H). I-O-49 402.1 0.73 ¹H NMR (500 MHz, DMSO-d6) δ 1.72(3H, m), 2.09 (1H, m), 2.28 (1H, m), 2.39 (3H, s), 2.79 (1H, m), 2.97(1H, m), 4.00 (1H, m), 4.25 (1H, m), 6.79 (2H, br s), 7.18 (1H, m), 8.19(1H, m), 8.54 (1H, m), 9.42 (1H, d), 9.47 (1H, s) and 9.81 (1H, s) ppmI-O-50 402.2 0.76 ¹H NMR (500 MHz, DMSO-d6) δ 1.72 (3H, m), 2.11 (1H,m), 2.27 (1H, m), 2.39 (3H, s), 2.78 (1H, m), 2.97 (1H, m), 4.00 (1H,m), 4.25 (1H, m), 6.79 (2H, br s), 7.19 (1H, m), 8.20 (1H, m), 8.54 (1H,m), 9.42 (1H, m), 9.47 (1H, s) and 9.81 (1H, s) ppm I-O-51 402.1 0.74 ¹HNMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.53 (s, 1H), 9.43 (d, J = 2.2Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.23 (d, J= 5.6 Hz, 1H), 6.78 (s, 2H), 4.69 (s, 1H), 2.92 (s, 1H), 2.59-2.47 (m,1H), 2.35-2.12 (m, 2H), 2.33 (s, 3H), 2.07 (d, J = 5.5 Hz, 1H), 1.91 (s,1H), 1.73-1.51 (m, 2H). I-O-52 390.1 0.68 ¹H NMR (500 MHz, DMSO-d6) δ10.06 (s, 1H), 9.51 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2Hz, 1H), 8.19 (d, J = 5.4 Hz, 1H), 7.13 (d, J = 5.5 Hz, 1H), 6.78 (s,2H), 4.22 (t, J = 5.9 Hz, 2H), 2.16 (s, 6H), 2.06 (p, J = 6.6 Hz, 2H).I-O-53 365.1 0.59 ¹H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.61 (s,1H), 9.47 (d, J = 2.2 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.52 (d, J =6.4 Hz, 1H), 7.60 (d, J = 6.4 Hz, 1H), 6.81 (s, 2H), 4.47 (t, J = 5.9Hz, 2H), 3.77 (s, 2H), 2.12 (p, J = 6.2 Hz, 2H). I-O-54 375.0 0.66 ¹HNMR (500 MHz, Methanol-d4) δ 10.29 (s, 1H), 9.61 (s, 1H), 8.88 (d, J =2.2 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 6.5 Hz, 1H), 7.56(d, J = 6.6 Hz, 1H), 5.47 (t, J = 4.9 Hz, 1H), 4.20 (dt, J = 11.0, 1.0Hz, 1H), 4.08-4.00 (m, 2H), 3.93 (td, J = 8.5, 4.2 Hz, 1H), 2.47-2.36(m, 1H), 2.27-2.18 (m, 1H). I-O-55 363.0 0.67 ¹H NMR (500 MHz,Methanol-d4) δ 10.44 (s, 1H), 9.70 (d, J = 1.2 Hz, 1H), 8.95 (d, J = 2.2Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.36 (dd, J = 6.7, 1.2 Hz, 1H), 7.59(d, J = 6.7 Hz, 1H), 4.60-4.55 (m, 2H), 3.96-3.90 (m, 2H), 3.39 (s, 3H).I-O-56 333.0 0.74 ¹H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.49 (s,1H), 9.42 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.19 (d, J =5.4 Hz, 1H), 7.13 (d, J = 5.5 Hz, 1H), 6.77 (s, 2H), 4.25 (q, J = 6.9Hz, 2H), 1.54 (t, J = 7.0 Hz, 3H). I-O-57 319.1 0.67 ¹H NMR (500 MHz,DMSO-d6) δ 4.28 (3H, s), 6.81 (2H, br s), 7.68 (1H, d), 8.60 (1H, d),8.81 (1H, d), 9.47 (1H, d), 9.61 (1H, s) and 10.34 (1H, s) ppm I-O-58375.0 0.66 ¹H NMR (500 MHz, Methanol-d4) δ 10.31 (s, 1H), 9.62 (s, 1H),8.89 (d, J = 2.2 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 6.6 Hz,1H), 7.57 (d, J = 6.6 Hz, 1H), 5.51-5.45 (m, 1H), 4.20 (d, J = 10.9 Hz,1H), 4.08-4.00 (m, 2H), 3.93 (td, J = 8.5, 4.2 Hz, 1H), 2.47-2.36 (m,1H), 2.29-2.18 (m, 1H). I-O-59 387.0 0.78 ¹H NMR (500 MHz, Methanol-d4)δ 10.41 (s, 1H), 9.79 (d, J = 1.1 Hz, 1H), 8.94 (dd, J = 2.1, 0.4 Hz,1H), 8.42 (dd, J = 6.6, 1.1 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 7.61 (d,J = 6.6 Hz, 1H), 5.10-5.01 (m, 2H) I-O-60 418.1 0.63 ¹H NMR (500 MHz,DMSO-d6) δ 9.91 (s, 1H), 9.47 (s, 1H), 9.43 (d, J = 2.2 Hz, 1H), 8.60(d, J = 2.2 Hz, 1H), 8.20 (d, J = 5.5 Hz, 1H), 7.20 (d, J = 5.5 Hz, 1H),6.78 (s, 2H), 4.35 (t, J = 5.9 Hz, 2H), 3.53 (t, J = 4.6 Hz, 4H), 2.90(t, J = 5.8 Hz, 2H), 2.52-2.50 (masked signal, 4H). I-O-61 389.0 0.68 ¹HNMR (500 MHz, Methanol-d4) δ 10.28 (s, 1H), 9.75 (d, J = 1.2 Hz, 1H),8.97 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.35 (dd, J = 6.7,1.3 Hz, 1H), 7.66 (d, J = 6.8 Hz, 1H), 5.15 (dt, J = 7.9, 4.0 Hz, 1H),4.05 (ddd, J = 10.8, 6.1, 3.9 Hz, 2H), 3.66 (ddd, J = 11.6, 8.2, 3.3 Hz,2H), 2.22-2.14 (m, 2H), 1.92 (ddt, J = 13.2, 8.5, 4.0 Hz, 2H). I-O-62414.0 0.69 ¹H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.53 (s, 1H), 9.41(d, J = 2.2 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H),7.06 (d, J = 5.5 Hz, 1H), 6.80 (s, 2H), 4.75-4.66 (m, 1H), 3.38 (d, J =4.0 Hz, 0H), 2.92-2.82 (m, 1H), 2.82-2.64 (m, 4H), 2.21 (dd, J = 4.9,1.8 Hz, 1H), 1.97 (ddd, J = 14.8, 11.1, 3.5 Hz, 1H), 1.76-1.66 (m, 1H),1.66-1.55 (m, 1H), 1.48-1.39 (m, 1H). I-O-63 388.0 0.69 ¹H NMR (500 MHz,DMSO-d6) δ 10.00 (s, 1H), 9.51 (s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 8.51(d, J = 2.2 Hz, 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.06 (d, J = 5.5 Hz, 1H),6.78 (s, 2H), 5.11-5.07 (m, 1H), 2.93 (dd, J = 10.7, 6.0 Hz, 1H),2.79-2.76 (m, 2H), 2.45-2.40 (m, 2H), 2.32 (s, 3H), 2.02-1.96 (m, 1H).I-O-64 402.0 0.66 ¹H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.52 (s,1H), 9.43 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.17 (d, J =5.5 Hz, 1H), 7.21 (d, J = 5.6 Hz, 1H), 6.79 (s, 2H), 4.66 (dq, J = 8.3,4.1 Hz, 1H), 2.71 (q, J = 5.5 Hz, 2H), 2.26 (t, J = 10.3 Hz, 2H), 2.20(s, 3H), 2.12-2.01(m, 2H), 1.82 (dtd, J = 12.6, 8.8, 3.6 Hz, 2H). I-O-65389.0 0.73 ¹H NMR (500 MHz, Methanol-d4) δ 10.47 (s, 1H), 9.74 (d, J =1.2 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H),8.37-8.32 (m, 1H), 7.59 (dd, J = 6.8, 2.1 Hz, 1H), 4.95-4.88 (m, 1H),4.00 (dd, J = 12.6, 3.8 Hz, 1H), 3.89 (dd, J = 12.5, 2.3 Hz, 1H), 3.82(dt, J = 11.1, 4.0 Hz, 1H), 3.64 (ddd, J = 11.3, 9.4, 2.8 Hz, 1H), 2.10(dt, J = 9.1, 4.3 Hz, 2H), 2.06-1.99 (m, 1H), 1.59 (dddd, J = 12.8, 7.6,4.6, 2.7 Hz, 1H). I-O-66 349.0 0.56 ¹H NMR (500 MHz, DMSO-d6) δ 10.18(s, 1H), 9.50 (s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 8.62 (d, J = 2.2 Hz,1H), 8.19 (d, J = 5.5 Hz, 1H), 7.16 (d, J = 5.5 Hz, 1H), 6.76 (s, 2H),4.92 (t, J = 5.1 Hz, 1H), 4.24 (t, J = 4.8 Hz, 2H), 3.94 (q, J = 4.9 Hz,2H). I-O-67 446.2 0.74 ¹H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.53(s, 1H), 9.43 (s, 1H), 8.56 (s, 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.22 (d,J = 5.6 Hz, 1H), 6.78 (s, 2H), 4.71-4.56 (m, 1H), 3.44 (dd, J = 6.5, 4.8Hz, 1H), 3.21 (s, 3H), 3.11 (dd, J = 12.8, 2.5 Hz, 1H), 2.76-2.46 (m,4H), 2.37 (d, J = 5.6 Hz, 1H), 2.30-2.20 (m, 1H), 2.13 (d, J = 11.0 Hz,1H), 1.86 (d, J = 8.5 Hz, 1H), 1.71-1.57 (m, 1H), 1.57-1.45 (m, 1H).I-O-68 410.0 0.76 ¹H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.71 (s,1H), 9.46 (d, J = 2.2 Hz, 1H), 9.30 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H),7.40 (s, 1H), 6.81 (s, 1H), 4.74-4.61 (m, 2H), 3.69 (s, 2H), 2.92 (s,6H). I-O-69 388.0 0.69 ¹H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.51(s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.17 (d, J= 5.5 Hz, 1H), 7.06 (d, J = 5.5 Hz, 1H), 6.78 (s, 2H), 5.11-5.07 (m,1H), 2.93 (dd, J = 10.7, 6.0 Hz, 1H), 2.79-2.76 (m, 2H), 2.45-2.40 (m,2H), 2.32 (s, 3H), 2.02-1.96 (m, 1H). I-O-70 382.0 0.67 ¹H NMR (500 MHz,DMSO-d6) δ 10.29 (s, 1H), 9.73 (s, 1H), 9.44 (d, J = 2.2 Hz, 1H), 8.71(dd, J = 2.9, 0.6 Hz, 1H), 8.66-8.55 (m, 2H), 8.41 (d, J = 6.0 Hz, 1H),7.84 (ddd, J = 8.4, 2.9, 1.3 Hz, 1H), 7.61 (ddd, J = 8.4, 4.8, 0.6 Hz,1H), 7.20 (d, J = 6.0 Hz, 1H), 6.82 (s, 2H). I-O-71 444.1 0.84 ¹H NMR(500 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.70 (br s, 1H), 9.68 (s, 1H), 9.48(d, J = 2.2 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 7.72 (s, 1H), 6.85 (s,2H), 4.84-4.69 (m, 2H), 3.71 (s, 2H), 2.92 (s, 6H). I-O-72 400.0 0.54 ¹HNMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.63 (s, 1H), 9.49 (dt, J = 2.8,1.4 Hz, 1H), 8.77 (s, 2H), 8.72 (dd, J = 2.1, 0.7 Hz, 1H), 8.52 (d, J =5.0 Hz, 1H), 7.38 (s, 1H), 6.83 (s, 2H), 5.06 (t, J = 6.3 Hz, 1H), 4.09(d, J = 3.1 Hz, 4H), 2.99 (dd, J = 13.8, 6.7 Hz, 2H), 2.55 (d, J = 5.6Hz, 2H). I-O-73 360.0 0.56 ¹H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H),9.57 (s, 1H), 9.46 (d, J = 2.2 Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.22(d, J = 5.4 Hz, 1H), 6.99 (d, J = 5.5 Hz, 1H), 6.80 (s, 2H), 5.32 (tt, J= 6.5, 4.5 Hz, 1H), 4.64-4.56 (m, 2H), 4.22-4.15 (m, 2H). I-O-74 388.20.62 ¹H NMR (500 MHz, Methanol-d4) δ 9.90 (d, J = 1.2 Hz, 1H), 9.11 (d,J = 2.2 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.56 (dd, J = 6.7, 1.2 Hz,1H), 7.84 (d, J = 6.7 Hz, 1H), 5.37 (dt, J = 7.8, 4.0 Hz, 1H), 3.69 (d,J = 4.1 Hz, 2H), 3.44-3.36 (m, 2H), 2.49 (ddq, J = 13.6, 8.9, 4.5 Hz,1H), 2.35 (ddt, J = 25.5, 11.3, 5.0 Hz, 2H), 2.22-2.06 (m, 1H). I-O-75388.1 0.65 ¹H NMR (500 MHz, Methanol-d4) δ 9.78 (d, J = 1.2 Hz, 1H),8.97 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.42 (dd, J = 6.7,1.3 Hz, 1H), 7.69 (d, J = 6.7 Hz, 1H), 5.24 (td, J = 5.1, 2.7 Hz, 1H),3.63-3.50 (m, 2H), 3.37-3.28 (m, 1H), 3.24-3.18 (m, 1H), 2.40 (dd, J =9.5, 4.7 Hz, 1H), 2.29-2.14 (m, 2H), 2.01 (dd, J = 10.3, 4.2 Hz, 1H).I-O-76 374.2 0.56 ¹H NMR (500 MHz, Methanol-d4) δ 9.90 (d, J = 1.2 Hz,1H), 9.11 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.57 (dd, J =6.7, 1.2 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 5.79 (q, J = 4.4, 3.5 Hz,1H), 3.91 (dd, J = 13.8, 4.7 Hz, 1H), 3.87-3.69 (m, 3H), 2.75-2.64 (m,2H). I-O-77 374.0 0.58 ¹H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.51(s, 1H), 9.43 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.19 (d, J= 5.5 Hz, 1H), 7.13 (d, J = 5.5 Hz, 1H), 6.78 (s, 2H), 5.17-5.10 (m,1H), 3.30-3.18 (m, 2H), 3.12-2.99 (m, 2H), 2.90 (ddd, J = 10.8, 8.0, 4.4Hz, 1H), 2.16-2.05 (m, 1H), 1.99-1.90 (m, 1H). I-O-78 400.0 0.6 ¹H NMR(500 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.50 (s, 1H), 9.42 (d, J = 2.1 Hz,1H), 8.63 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 5.4 Hz, 1H), 6.99 (d, J =5.4 Hz, 1H), 6.77 (s, 2H), 4.64 (p, J = 6.9 Hz, 1H), 3.33 (m, 2H), 2.93(ddd, J = 9.9, 6.7, 3.3 Hz, 2H), 2.32 (t, J = 7.1 Hz, 2H), 2.24 (ddd, J= 10.0, 7.2, 3.5 Hz, 2H). I-O-79 400.0 0.6 ¹H NMR (500 MHz, DMSO-d6) δ9.55 (s, 1H), 9.45 (dd, J = 2.2, 0.6 Hz, 1H), 9.02 (s, 2H), 8.71 (d, J =2.2 Hz, 1H), 8.23 (d, J = 5.4 Hz, 1H), 6.92 (d, J = 5.5 Hz, 1H), 6.80(d, J = 3.6 Hz, 2H), 5.04 (tt, J = 6.7, 4.7 Hz, 1H), 3.83 (t, J = 8.2Hz, 2H), 3.27 (dd, J = 14.7, 6.8 Hz, 2H), 2.66-2.56 (m, 4H). I-O-80388.0 0.56 ¹H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.52 (s, 1H), 9.42(d, J = 2.2 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H),7.21 (d, J = 5.6 Hz, 1H), 6.78 (s, 2H), 4.77 (tt, J = 7.9, 3.5 Hz, 1H),3.11-3.03 (m, 2H), 2.65 (ddd, J = 12.4, 9.0, 3.1 Hz, 2H), 1.98 (ddt, J =12.9, 6.5, 3.6 Hz, 2H), 1.65 (dtt, J = 12.4, 9.2, 3.4 Hz, 2H). I-O-81388.2 0.62 ¹H NMR (500 MHz, Methanol-d4) δ 9.90 (d, J = 1.2 Hz, 1H),9.11 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.55 (dd, J = 6.7,1.2 Hz, 1H), 7.83 (d, J = 6.7 Hz, 1H), 5.42-5.31 (m, 1H), 3.69 (d, J =4.1 Hz, 2H), 3.48-3.35 (m, 2H), 2.49 (ddq, J = 13.5, 8.8, 4.5 Hz, 1H),2.43-2.25 (m, 2H), 2.21-2.08 (m, 1H). I-O-82 365.1 0.49 ¹H NMR (500 MHz,DMSO-d6) δ 10.34 (s, 1H), 9.66 (s, 1H), 9.33 (s, 1H), 9.20-9.01 (m, 2H),8.76 (d, J = 2.0 Hz, 1H), 8.46 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 5.9 Hz,1H), 6.79 (s, 2H), 5.56-5.38 (m, 1H), 4.66 (p, J = 6.5, 6.1 Hz, 2H),4.25 (dd, J = 13.6, 6.9 Hz, 2H), 4.14 (s, 2H). I-O-83 353.1 0.49 ¹H NMR(500 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.60 (s, 1H), 9.11 (dd, J = 1.9, 0.9Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 6.1 Hz, 1H), 8.15 (s,3H), 7.59 (d, J = 6.1 Hz, 1H), 6.77 (s, 2H), 4.61 (t, J = 4.9 Hz, 2H),4.12 (s, 2H), 3.49 (q, J = 5.2, 4.6 Hz, 2H). I-O-84 393.1 0.52 ¹H NMR(500 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.55 (s, 1H), 9.06 (dt, J = 1.5, 0.7Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.20 (d, J= 5.6 Hz, 1H), 6.74 (s, 2H), 4.77 (tt, J = 7.7, 3.5 Hz, 1H), 4.14 (s,2H), 3.13-3.02 (m, 2H), 2.74-2.62 (m, 2H), 2.06-1.95 (m, 2H), 1.74-1.61(m, 2H). I-O-85 372.2 0.60 — I-O-86 377.1 0.51 ¹H NMR (500 MHz, DMSO-d6)δ 10.08 (s, 1H), 9.52 (s, 1H), 9.04 (dd, J = 2.0, 0.9 Hz, 1H), 8.55 (d,J = 2.0 Hz, 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.11 (d, J = 5.5 Hz, 1H),6.72 (s, 2H), 5.12 (ddt, J = 6.7, 4.6, 2.0 Hz, 1H), 4.14 (s, 2H), 3.20(dd, J = 12.6, 5.1 Hz, 1H), 3.12-3.01 (m, 2H), 2.90 (ddd, J = 10.9, 8.1,4.5 Hz, 1H), 2.12 (dtd, J = 14.0, 8.0, 6.2 Hz, 1H), 1.97 (dqd, J = 13.4,4.3, 2.0 Hz, 1H). I-O-87 379.1 0.51 ¹H NMR (500 MHz, DMSO-d6) δ 10.07(s, 1H), 9.53 (s, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.1 Hz,1H), 8.17 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 5.5 Hz, 1H), 6.72 (s, 2H),5.18-5.07 (m, 1H), 4.15 (s, 2H), 3.28-3.17 (m, 1H), 3.15-3.02 (m, 2H),2.99-2.86 (m, 1H), 2.21-2.07 (m, 1H), 2.02-1.93 (m, 1H). I-O-88 345.01.16* ¹H NMR (500 MHz, DMSO-d6) δ 1.74 (9H, s), 6.79 (2H, s), 7.82-7.83(1H, d), 8.45-8.46 (1H, d), 8.74-8.75 (1H, d), 9.53-9.54 (1H, dd),9.68-9.69 (1H, d), 10.29 (1H, s). I-O-89 404.1 2.23* ¹H NMR (500 MHz,DMSO-d6) δ 1.99-2.15 (2H, m), 2.27-2.37 (2H, m), 2-76-2.79 (3H, m),3.09-3.30 (2H, m), 3.46-3.57 (2H, m), 4.74 (1H, m), 6.78 (2H, br s),8.36 (1H, d), 8.83-8.88 (1H, m), 9.45-9.54 (2H, m), 9.77 (1H, m) and10.09 (1H, s) ppm rotamers observed. I-O-90 332.1 1.88* ¹H NMR (500 MHz,DMSO-d6) δ 12.47 (s, 1H), 9.91 (s, 1H), 9.50 (dd, J = 4.8, 2.6 Hz, 1H),8.89 (d, J = 2.5 Hz, 1H), 8.74 (s, 1H), 6.69 (s, 2H), 6.50 (s, 1H), 4.12(s, 3H), 2.94 (d, J = 4.7 Hz, 3H). I-O-91 446.1 2.06* ¹H NMR (500 MHz,DMSO-d6) δ 1.85 (2H, m), 1.92-2.08 (4H, m), 2.67 (2H, m), 4.40 (2H, m),4.49 (2H, m), 4.61 (1H, m), 6.77 (2H, br s), 8.30 (1H, m), 8.82 (1H, m),9.47 (1H, s), 9.52 (1H, m) and 10.03 (1H, s) ppm Oxetane CH notobserved. I-O-92 345.0 1.76* ¹H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H),9.68 (s, 1H), 9.53 (dd, J = 4.8, 2.5 Hz, 1H), 8.96-8.85 (m, 1H), 8.48(s, 1H), 7.25 (s, 1H), 6.78 (s, 2H), 5.71 (tt, J = 5.9, 4.5 Hz, 1H),5.10 (ddd, J = 7.8, 5.9, 1.1 Hz, 2H), 4.79 (ddd, J = 7.9, 4.5, 1.0 Hz,2H). Retention times measured using HPLC Method B, described in theExperimental Methods and Materials section, above., are designated by(*). For all other compounds, the retention time was measured using theHPLC Method A.

Preparation C-1 4-(1-methylpiperidin-4-yl)pyridin-3-amine

Step 1: 4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-nitro-pyridine

To a solution of 4-chloro-3-nitro-pyridine (350 mg, 2.208 mmol) inToluene (7.00 mL), Ethanol (1.75 mL) and sodium carbonate solution (aq)(2.21 mL of 1 M, 2.21 mmol) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine(985.3 mg, 4.416 mmol), Pd₂(dba)₃ (60.66 mg, 0.07 mmol) and triphenylphosphine (115.8 mg, 102.3 μL, 0.44 mmol). The mixture was stirred at75° C. (reflux) for 18 hours. The reaction mixture was evaporated todryness and the residue was partitioned between water (30 mL) and DCM(2×30 mL). The combined organics were washed with water (30 mL) andbrine (30 mL), dried and evaporated to dryness to afford a dark brownoil which was purified by column chromatography on silica gel elutingwith petroleum ether (A): ethyl acetate (B) (20-100% (B), 24 g, 30.0 CV,35 mL/min) then ethyl acetate (A): methanol (B) (0-10% (B)) to afford4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-nitro-pyridine as a red oil(305 mg, 63%). MS (ES+) 220.1.

Step 2: 4-(1-methylpiperidin-4-yl)pyridin-3-amine

To a solution of4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-nitro-pyridine (300 mg, 1.37mmol) in Methanol (3.00 mL) was added Pd on C, (10%, wet, Degussa)(29.12 mg, 0.274 mmol) and the mixture was stirred at ambienttemperature under an atmosphere of hydrogen, for 18 hours. The catalystwas filtered off and the filtrate was concentrated in vacuo to afford4-(1-methylpiperidin-4-yl)pyridin-3-amine. MS (ES+) 192.1.

The following aminopyridine were synthesized according to PreparationC-1:

-   4-(tetrahydrofuran-3-yl)pyridin-3-amine:

Preparation C-2 tert-butyl5-amino-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate

Step 1:7-tert-butoxycarbonyl-6,8-dihydro-5H-2,7-naphthyridine-4-carboxylic acid

To a solution of 5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid(Hydrochloric Acid (2)) (1 g, 3.982 mmol) in a mixture of NaHCO₃ (1.673g, 19.91 mmol) in water (20.00 mL) and dioxane (20.00 mL), was addedBoc₂O (869.1 mg, 914.8 μL, 3.982 mmol), and the mixture was stirredovernight at RT. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in ethyl acetate and water mixture and the pH ofthe aqueous phase was adjusted to pH4 using a sodium bisulfate solution.The organic and aqueous layers were separated, the organic layer washedwith brine, dried over MgSO₄, and concentrated under reduced pressure toyield7-tert-butoxycarbonyl-6,8-dihydro-5H-2,7-naphthyridine-4-carboxylic acid(440 mg, 40%). MS (ES+) 279.2.

Step 2: tert-butyl5-amino-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate

To a solution of7-tert-butoxycarbonyl-6,8-dihydro-5H-2,7-naphthyridine-4-carboxylic acid(440 mg, 1.581 mmol) in NMP (6 mL) was added TEA (207.9 mg, 286.4 μL,2.055 mmol) followed by diphenylphosphoryl azide (478.6 mg, 374.8 μL,1.739 mmol) at rt under nitrogen. The reaction was heated to 90° C. for2 hours. At RT, the reaction mixture was partitioned between an aqueoussaturated solution of NaHCO₃ and EtOAc. Combined organic extract waswashed with brine, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by chromatography on silica, elutingwith 1-15% MeOH:DCM to yield tert-butyl5-amino-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate. (397 mg,100.7%). MS (2ES+) 501.2.

Preparation C-3 [4,4′-bipyridin]-3-amine

4-chloro-3-nitro-pyridine (100 mg, 0.6307 mmol), 4-pyridylboronic acid(77.52 mg, 0.6307 mmol), palladium; triphenylphosphane (36.45 mg,0.03154 mmol), K₃PO₄ (946.0 μL of 2 M, 1.892 mmol) in dioxane (3 mL) washeated at 130° C. for 30 min in a microwave. The mixture was loaded on aSCX column, washed with MeOH. The product was eluted with a 2M NH₃ inMeOH. The filtrate was concentrated in vacuo. The residue was dissolvedin MeOH (20 mL), Pd/C 10% (42.04 mg, 0.3950 mmol) was added and themixture was hydrogenated (H₂ balloon) overnight. The catalyst wasfiltered off and the filtrate was concentrated in vacuo yielding[4,4′-bipyridin]-3-amine that was used in next step without furtherpurification. MS (ES+) 172.1.

Preparation C-4 3′-methyl-[4,4′-bipyridin]-3-amine

[3-(tert-butoxycarbonylamino)-4-pyridyl]boronic acid (100 mg, 0.4201mmol), palladium; triphenylphosphane (48.55 mg, 0.04201 mmol),4-bromo-3-methyl-pyridine (113.9 mg, 0.5461 mmol), K₃PO₄ (630.0 μL of 2M, 1.260 mmol), in dioxane (4.000 mL) was heated at 130° C. for 30 minin a MW. The reaction mixture was partitioned between water and DCM.Combined organic extract was dried and concentrated in vacuo. Theresidue was dissolved in DCM (10 mL) and TFA (2 mL) was added. After 1h, the reaction mixture was concentrated in vacuo. The residue wasloaded on a SCX column, washed with MeOH. The product was eluted with a2M NH₃ in MeOH, filtrate was concentrated in vacuo yielding3′-methyl-[4,4′-bipyridin]-3-amine that was used in next reaction w/ofurther purification (90 mg). MS (ES+) 172.1.

The following amino pyridine were prepared using procedures similar toPreparation C-3 or Preparation C-4:

Preparation C-5 4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine

Step 1: tert-butyl3′-nitro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate

4-chloro-3-nitro-pyridine (1 g, 6.307 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(2.145 g, 6.938 mmol) and PdCl₂(PPh₃)₂ (221.4 mg, 0.3154 mmol) in DME(20.00 mL) were degassed using 3× vacuum/nitrogen cycles. Na₂CO₃ (9.460mL of 2 M, 18.92 mmol) was added followed by further degassing and thereaction heated at 80° C. for 18 hours. The reaction was cooled toambient temperature and diluted with EtOAc/water. The layers wereseparated and the aqueous layer was extracted with EtOAc (×3). Thecombined organic extracts were washed with brine (×1), dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (ISCO Companion, 120 g column, eluting with 0 to 70%EtOAc/Petroleum Ether, dry loaded) to give tert-butyl3′-nitro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate as a paleyellow solid (884 mg, 46% Yield). MS (ES Na+) 328.1.

Step 2: 3′-nitro-1,2,3,6-tetrahydro-4,4′-bipyridine

TFA (2 mL, 25.96 mmol) was added to a stirred solution of tert-butyl4-(3-nitro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (883 mg,2.892 mmol) in DCM (10 mL) and the reaction stirred at ambienttemperature for 15 hours. The solvent was removed in vacuo and theresidue azeotroped with DCM (×2) and ether (×2). The residue was passedthrough a 25 g SCX-2 cartridge and washed with MeOH/DCM mixtures. Theproduct was eluted by washing the cartridge with 2M NH₃ in MeOH/DCMmixtures and concentrated in vacuo to give3′-nitro-1,2,3,6-tetrahydro-4,4′-bipyridine as an orange oil (523 mg,88% Yield). MS (ES+) 206.1.

Step 3: 3′-nitro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine

Sodium triacetoxyborohydride (Sodium Ion (1)) (1.189 g, 5.608 mmol) wasadded in portions to a stirred solution of3-nitro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (523 mg, 2.549 mmol)and 3-oxetanone (312.2 mg, 277.8 μL, 4.333 mmol) in THF (10 mL) at 0° C.under an atmosphere of nitrogen. The reaction was allowed to warm toambient temperature and was stirred for 16 hours. MeOH (2 mL) was addeddropwise and the mixture stirred at ambient temperature for 30 minutes.The mixture was concentrated in vacuo and the residue was partitionedbetween water and EtAOc. The pH of the aqueous layer was adjusted to pH7-8 by the addition of NH₄OH and the layers separated. The aqueous layerwas extracted with EtOAc (×3) and the combined organic extracts washedwith brine (×1), dried (MgSO₄), filtered and concentrated in vacuo togive 3′-nitro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine as ared oil (615 mg, 92% Yield). MS (ES+) 262.1.

Step 4: 4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine

Pd on C, wet, Degussa (240 mg, 0.2255 mmol) was added to a stirredsolution of3-nitro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine (614 mg,2.350 mmol) in EtOAc (20 mL)/EtOH (20 mL). The reaction was placed underan atmosphere of hydrogen and stirred at ambient temperature for 15hours. The catalyst was removed by filtration through a pad of celiteand the filtrate concentrated in vacuo to give the4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine as a pale yellow solid(518 mg, 95% Yield). MS (ES+) 234.2.

Preparation C-6 5-fluoro-4-(1-methylpiperidin-4-yl)pyridin-3-amine

Step 1: 3′-chloro-5′-fluoro-1-methyl-1,2,3,6-tetrahydro-4,4′-bipyridine

3-chloro-5-fluoro-4-iodo-pyridine (500 mg, 1.942 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine(476.6 mg, 2.136 mmol) and Pd(PPh₃)₂Cl₂ (68.15 mg, 0.09710 mmol) in DME(10.00 mL) were degassed using 3×vacuum/nitrogen cycles. Na₂CO₃ (2.913mL of 2 M, 5.826 mmol) was added followed by further degassing and thereaction heated at 80° C. for 18 hours. The reaction was cooled toambient temperature and diluted with EtOAc/water. The layers wereseparated and the aqueous layer extracted with EtOAc (×3). The combinedorganic extracts were washed with brine (×1), dried (MgSO₄), filteredand concentrated in vacuo. The residue was passed through a 10 g SCX-2cartridge and washed with MeOH/DCM mixtures. The product was eluted bywashing the cartridge with 2M NH₃ in MeOH/DCM mixtures and concentratedin vacuo. The residue was purified by column chromatography (ISCOCompanion, 40 g column, eluting with 0 to 10% MeOH/DCM+1% NH₄OH, loadedin DCM) to give3′-chloro-5′-fluoro-1-methyl-1,2,3,6-tetrahydro-4,4′-bipyridine as a redsolid (378 mg, 86% Yield). MS (ES+) 227.1.

Step 2: tert-butyl(5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate

3-chloro-5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridine (377mg, 1.663 mmol), tert-butyl carbamate (974.1 mg, 8.315 mmol), sodiumtert-butoxide (815.1 mg, 8.481 mmol), BrettPhos pre-catalyst (66.25 mg,0.08315 mmol) and BrettPhos (44.63 mg, 0.08315 mmol) were placed in asealable tube an degassed by vacuum/nitrogen cycles (×5). Dry dioxane(10 mL) was added and the resulting mixture was placed into a pre-heatedblock at 100° C. and stirred at this temperature for 16 hours. Furtherportions of BrettPhos pre-catalyst (66.25 mg, 0.08315 mmol) andBrettPhos (44.63 mg, 0.08315 mmol) were added and the reaction heated at100° C. for 8 hours. The reaction mixture was cooled to ambienttemperature and quenched with saturated NH₄Cl. The mixture was passedthrough a pre-wetted (EtOAc) celite cartridge (2.5 g). The cartridge waswashed with EtOAc/saturated NH₄Cl and the layers of the filtrateseparated. The aqueous layer was extracted with EtOAc (×3) and thecombined organic extracts were washed with brine (×1), dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (ISCO Companion, 40 g column, eluting with 0 to 10%MeOH/DCM, loaded in DCM) to give tert-butyl(5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate.MS (ES+) 308.2.

Step 3:5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-amine

TFA (2 mL, 25.96 mmol) was added to a stirred solution of tert-butylN-[5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl]carbamate(483 mg, 1.571 mmol) in DCM (10 mL) and the reaction stirred at ambienttemperature for 6 hours. The solvent was removed in vacuo and theresidue azeotroped with DCM (×2) and ether (×2). The residue was passedthrough a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. Theproduct was eluted by washing the cartridge with 2M NH₃ in MeOH/DCMmixtures and concentrated in vacuo. The residue was purified by columnchromatography (ISCO Companion, 40 g column, eluting with 0 to 10%MeOH/DCM+1% NH₄OH, loaded in DCM) to give5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-amine as anoff-white solid (61 mg, 19% Yield over 2 steps). MS (ES+) 208.1.

Step 4: 5-fluoro-4-(1-methylpiperidin-4-yl)pyridin-3-amine

Pd on C, wet, Degussa (25 mg, 0.1175 mmol) was added to a stirredsolution of5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridin-3-amine (61 mg,0.2943 mmol) in EtOAc (5 mL)/EtOH (5 mL). The reaction was placed underan atmosphere of hydrogen and stirred at ambient temperature for 15hours. A further portion of Pd on C, wet, Degussa (25 mg, 0.1175 mmol)was added and the reaction was placed under an atmosphere of hydrogenand stirred at ambient temperature for 24 hours. The catalyst wasremoved by filtration through a pad of celite and the filtrateconcentrated in vacuo to give5-fluoro-4-(1-methylpiperidin-4-yl)pyridin-3-amine as an off-white solid(58 mg, 95% Yield). MS (ES+) 210.1.

Preparation C-75-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine

Step 1: tert-butyl3′-chloro-5′-fluoro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate

3-chloro-5-fluoro-4-iodo-pyridine (750 mg, 2.913 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(990.7 mg, 3.204 mmol) and Pd(PPh₃)₂Cl₂ (102.2 mg, 0.1456 mmol) in DME(15 mL) were degassed using 3×vacuum/nitrogen cycles. Na₂CO₃ (4.370 mLof 2 M, 8.739 mmol) was added followed by further degassing and thereaction heated at 90° C. for 2 hours. The reaction was cooled toambient temperature and diluted with EtOAc/water. The layers wereseparated and the aqueous layer extracted with EtOAc (×3). The combinedorganic extracts were washed with brine (×1), dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by columnchromatography (ISCO Companion, 80 g column, eluting with 0 to 20%EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl3′-chloro-5′-fluoro-5,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate asan off-white solid (708 mg, 78% Yield). MS (ES+) 313.1.

Step 2: 3′-chloro-5′-fluoro-1,2,3,6-tetrahydro-4,4′-bipyridine

TFA (2 mL, 25.96 mmol) was added to a stirred solution of tert-butyl4-(3-chloro-5-fluoro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate(708 mg, 2.264 mmol) in DCM (10 mL) and the reaction stirred at ambienttemperature for 2 hours. The solvent was removed in vacuo and theresidue azeotroped with DCM (×2) and ether (×2). The residue was passedthrough a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. Theproduct was eluted by washing the cartridge with 2M NH₃ in MeOH/DCMmixtures and concentrated in vacuo to give3′-chloro-5′-fluoro-1,2,3,6-tetrahydro-4,4′-bipyridine as an off-whitesolid (468 mg, 97% Yield). MS (ES+) 213.1.

Step 3:3′-chloro-5′-fluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridine

Sodium triacetoxyborohydride (Sodium Ion (1)) (1.026 g, 4.842 mmol) wasadded in portions to a stirred solution of3-chloro-5-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (468 mg,2.201 mmol) and 3-oxetanone (269.7 mg, 239.9 μL, 3.742 mmol) in THF (10mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowedto warm to ambient temperature over 16 hours. MeOH (2 mL) was addeddropwise and the mixture stirred at ambient temperature for 30 minutes.The mixture was concentrated in vacuo and partitioned between water andEtAOc. The pH of the aqueous layer was adjusted to p H 7-8 by theaddition of NH₄OH and the layers separated. The aqueous layer wasextracted with EtOAc (×3) and the combined organic extracts washed withbrine (×1), dried (MgSO₄), filtered and concentrated in vacuo to give3′-chloro-5′-fluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydro-4,4′-bipyridineas a white solid (573 mg, 97% Yield). MS (ES+) 269.1.

Step 4: tert-butyl(5-fluoro-1′-(oxetan-3-yl)-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate

3-chloro-5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine(572 mg, 2.129 mmol), tert-butyl carbamate (1.246 g, 10.64 mmol), sodiumtert-butoxide (1.044 g, 10.86 mmol), BrettPhos pre-catalyst (84.78 mg,0.1064 mmol) and BrettPhos (57.11 mg, 0.1064 mmol) were placed in asealable tube and degassed by vacuum/nitrogen cycles (×5). Dry dioxane(10 mL) was added and the resulting mixture was placed into a pre-heatedblock at 100° C. and stirred at this temperature for 16 hours. Thereaction mixture was cooled to ambient temperature and quenched withsaturated NH₄Cl. The mixture was passed through a pre-wetted (EtOAc)celite cartridge (2.5 g). The cartridge was washed with EtOAc/saturatedNH₄Cl and the layers of the filtrate separated. The aqueous layer wasextracted with EtOAc (×3) and the combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby column chromatography (ISCO Companion, 80 g column, eluting with 0 to100% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl(5-fluoro-1′-(oxetan-3-yl)-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamateas a pale yellow solid (180 mg, 24% Yield). Also isolate 197 mg of amixture of SM and product. MS (ES+) 350.2.

Step 5: tert-butyl(5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-yl)carbamate

Pd on C, wet, Degussa (70 mg, 0.06578 mmol) was added to a stirredsolution of tert-butylN-[5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-3-pyridyl]carbamate(180 mg, 0.5152 mmol) in EtOH (5 mL)/EtOAc (5 mL). The reaction wasplaced under an atmosphere of hydrogen and stirred at ambienttemperature for 46 hours. The catalyst was removed by filtration througha pad of celite and the filtrate concentrated in vacuo to givetert-butyl(5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-yl)carbamate as anoff-white solid (175 mg, 97% Yield). MS (ES+) 352.2.

Step 6: 5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine

TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butylN-[5-fluoro-4-[1-(oxetan-3-yl)-4-piperidyl]-3-pyridyl]carbamate (174 mg,0.4951 mmol) in DCM (5 mL) and the reaction stirred at ambienttemperature for 4 hours. The solvent was removed in vacuo and theresidue azeotroped with DCM (×2) and ether (×2). The residue was passedthrough a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. Theproduct was eluted by washing the cartridge with 2M NH₃ in MeOH/DCMmixtures and concentrated in vacuo to give5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine as a yellowoil (109 mg, 88% Yield). MS (ES+) 252.1.

Preparation C-8(3′-amino-5′-fluoro-5,6-dihydro-[4,4′-bipyridin]-1(2H)-yl)(1-methylpiperidin-4-yl)methanone

Step 1:(3′-chloro-5′-fluoro-5,6-dihydro-[4,4′-bipyridin]-1(2H)-yl)(1-methylpiperidin-4-yl)methanone

To a solution of3-chloro-5-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)pyridine (540 mg,2.539 mmol) (prepared according to methods similar to the ones depictedin step 1 and step 2 of Preparation C-7) in NMP (5 mL) was added TBTU(1.223 g, 3.809 mmol), 1-methylpiperidine-4-carboxylic acid(Hydrochloric Acid (1)) (547.4 mg, 3.047 mmol) and DIPEA (656.3 mg,884.5 μL, 5.078 mmol) and the reaction was stirred at ambienttemperature for 2 hours. The reaction mixture was adsorbed onto apre-wetted (methanol, 20 mL) SCX-2 cartridge (10 g) and flushed withDCM/methanol (1:1, 2×20 mL) and then the basic components eluted with 2M ammonia in methanol (2×20 mL). The basic eluent was evaporated todryness to afford a pale orange oil (744 mg). The residue was trituratedin DCM (2 mL) and a white solid was filtered off. The filtrate waspurified by column chromatography on silica gel eluting with DCM (A):DCM/Methanol/NH₄OH (90:10:1, (B)) (0-100% (B), 40 g, 20.0 CV, 40 mL/min)to afford(3′-chloro-5′-fluoro-5,6-dihydro-[4,4′-bipyridin]-1(2H)-yl)(1-methylpiperidin-4-yl)methanoneas a pale orange oil (410 mg, 48%). MS (ES+) 338.5.

Step 2:(3′-amino-5′-fluoro-5,6-dihydro-[4,4′-bipyridin]-1(2H)-yl)(1-methylpiperidin-4-yl)methanone

[4-(3-chloro-5-fluoro-4-pyridyl)-3,6-dihydro-2H-pyridin-1-yl]-(1-methyl-4-piperidyl)methanone(400 mg, 1.184 mmol), tert-butyl carbamate (693.5 mg, 5.920 mmol),BrettPhos (63.55 mg, 0.1184 mmol), BrettPhos pre-catalyst (94.34 mg,0.1184 mmol) and sodium tert-butoxide (580.3 mg, 6.038 mmol) were addedto a Schlenk tube under a nitrogen atmosphere. The solid mixture wasdegassed by vacuum/nitrogen cycles (×5) then was added anhydrous Toluene(8.000 mL) and the resulting mixture was placed into a pre-heated blockat 100° C. and was stirred for 4 hours. The reaction mixture was cooledto ambient temperature, quenched with saturated NH₄Cl solution andpartitioned between DCM/MeOH (9:1, 2×50 mL) and water (50 mL). Thecombined organics were washed with brine (50 mL), dried and concentratedin vacuo to afford a pale orange oil (456 mg). The residue was purifiedby column chromatography on silica gel eluting with DCM (A):DCM/MeOH/NH₄ OH (90:10:1, (B)) (0-100% (B), 40 g, 20.0 CV, 40 mL/min) toafford(3′-amino-5′-fluoro-5,6-dihydro-[4,4′-bipyridin]-1(2H)-yl)(1-methylpiperidin-4-yl)methanone(200 mg). It was dissolved in DCM (2.000 mL) and TFA (1.0 mL) was addedand the mixture was stirred at ambient temperature overnight. Thereaction mixture was concentrated in vacuo and the residue was loadedonto a pre-wetted (DCM/methanol, (1:1) 10 mL) SCX-2 cartridge (5 g) andflushed with DCM/methanol (1:1, 25 mL) and then the basic components waseluted with 2 M ammonia in methanol (20 mL). The basic eluent wasevaporated to dryness to afford a pale yellow oil (325 mg) that waspurified by column chromatography on silica gel eluting with DCM (A):DCM/Methanol/NH₄OH (90:10:1, (B)) (50-100% (B), 2 4 g, 20.0 CV, 35mL/min) to afford(3′-amino-5′-fluoro-5,6-dihydro-[4,4′-bipyridin]-1(2H)-yl)(1-methylpiperidin-4-yl)methanoneas a colourless oil (55 mg, 12%). MS (ES+) 319.2.

Preparation C-9 4-(3-aminopyridin-4-yl)-1-methylpiperidin-2-one

Step 1: tert-butyl(1′-methyl-2′-oxo-1′,2′-dihydro-[4,4′-bipyridin]-3-yl)carbamate

To a suspension of [3-(tert-butoxycarbonylamino)-4-pyridyl]boronic acid(200 mg, 0.8402 mmol), 4-bromo-1-methyl-pyridin-2-one (158.0 mg, 0.8402mmol) and Pd(PPh₃)₄ (48.55 mg, 0.04201 mmol) in Dioxane (2 mL) was addedNa₂CO₃ (840.0 μL of 2 M, 1.680 mmol) and was heated at 80° C. overnight.The reaction mixture was cooled to ambient temperature and filteredthrough a prewetted (methanol, 5 mL) Celite cartridge (2.5 g) and washedwith methanol (35 mL). The filtrate was concentrated in vacuo to afforda pale brown oil (500 mg). The residue was partitioned between DCM (2×30mL) and saturated sodium bicarbonate solution (30 mL). The combinedorganics were dried (phase sep cartridge) and concentrated in vacuo toafford an orange oil (280 mg). The residue was purified by columnchromatography on ISCO Companion eluting with DCM (A):DCM/Methanol/NH₄OH (90:10:1, (B)) (0-100% (B), 12 g, 16.0 CV, 30 mL/min)to afford tert-butyl(1′-methyl-2′-oxo-1′,2′-dihydro-[4,4′-bipyridin]-3-yl)carbamate as apale yellow oil (121 mg, 48%). MS (ES+) 302.1.

Step 2: tert-butyl(4-(1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)carbamate

A 0.05 M solution of tert-butylN-[4-(1-methyl-2-oxo-4-pyridyl)-3-pyridyl]carbamate (120 mg, 0.3982mmol) in Ethanol (8 mL) was passed through a Pd/C CatCart in the H-cubeat a flow rate of 0.5 mL/min at 50 C and 50 bar. The procedure wasrepeated 3 more time. The product solution was concentrated in vacuo toafford tert-butyl(4-(1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)carbamate as a colourlessoil (74 mg, 61%). MS (ES+) 306.1.

Step 3: 4-(3-aminopyridin-4-yl)-1-methylpiperidin-2-one

TFA (0.75 mL, 9.735 mmol) was added to a solution of tert-butylN-[4-(1-methyl-2-oxo-4-piperidyl)-3-pyridyl]carbamate (74 mg, 0.2423mmol) in DCM (2 mL) and was stirred at ambient temperature for 2 hours.The reaction mixture was adsorbed onto a pre-wetted (methanol/DCM (1:1),2 mL) SCX-2 cartridge (2 g) and flushed with DCM/methanol (1:1, 20 mL)and then the basic components eluted with 2 M ammonia in methanol (20mL). The basic eluent was evaporated to dryness to afford4-(3-aminopyridin-4-yl)-1-methylpiperidin-2-one as a pale yellow oil (50mg, 97%). MS (ES+) 206.1.

Preparation C-10 1-((3-aminopyridin-4-yl)methyl)pyrrolidin-2-one

Step 1: 1-((3-bromopyridin-4-yl)methyl)pyrrolidin-2-one

Solution A: Sodium hydride (141.5 mg, 3.537 mmol) was added to asolution of pyrrolidin-2-one (316.1 mg, 282.2 μL, 3.714 mmol) in THF (5mL) and the solution was stirred for 30 mins.

Solution B: To a solution of (3-bromo-4-pyridyl)methanol (665 mg, 3.537mmol) in DCM (20 mL) at 0° C. was added triethylamine (0.467 mL, 3.351mmol) and methanesulfonyl chloride (0.287 mL, 3.708 mmol) and thesolution allowed to warm to room temperature and stirred for 1 h.

Solution B was added to Solution A and the mixture was stirred for 2 h.The reaction mixture was partitioned between water and EtOAc. Combinedorganic extract was washed with brine, dried (MgSO₄) and concentrated invacuo (at RT) to give a oil that was purified by chromatography onsilica (eluting with 2-4% MeOH in EtOAc) to give1-((3-bromopyridin-4-yl)methyl)pyrrolidin-2-one as a yellow oil. MS(ES+) 211.0.

Step 2: 1-((3-aminopyridin-4-yl)methyl)pyrrolidin-2-one

Prepared according to a procedure similar to Step 3 of Preparation N-14.MS (ES+) 192.0.

The following amides were formed using a procedure similar to Example 1or Example 3a:

-   2-amino-6-fluoro-N-(4-(1-methylpiperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-1);-   2-amino-6-chloro-N-(4-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-2);-   2-amino-6-(cyanomethyl)-N-(4-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-3);-   2-amino-6-fluoro-N-(4-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-4);-   2-amino-6-fluoro-N-(4-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-5);-   2-amino-6-(cyanomethyl)-N-(4-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-6);-   2-amino-6-fluoro-N-(5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-7);-   2-amino-6-fluoro-N-(4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-10);-   2-amino-6-chloro-N-(4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-11);-   2-amino-6-fluoro-N-(5-fluoro-1′-(oxetan-3-yl)-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-12);-   2-amino-6-fluoro-N-(5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-13);-   2-amino-6-fluoro-N-(5-fluoro-4-(1-methylpiperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-14);-   N-([3,4′-bipyridin]-3′-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-15);-   2-amino-6-fluoro-N-(6-(4-methylpiperazine-1-carbonyl)-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-19);-   2-amino-6-fluoro-N-(2-methyl-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-20)-   2-amino-6-fluoro-N-(6-(4-methylpiperazin-1-yl)-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-21);-   2-amino-6-fluoro-N-(6-methyl-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-22);-   2-amino-6-(2-cyanopropan-2-yl)-N-(4-(1-methylpiperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-23);-   N-([4,4′-bipyridin]-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-24);-   2-amino-6-fluoro-N-(4-(4-(4-methylpiperazine-1-carbonyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-25);-   2-amino-6-fluoro-N-(4-(pyridazin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-26);-   2-amino-6-fluoro-N-(6-methoxy-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-27);-   2-amino-6-fluoro-N-(4-(pyrimidin-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-28);-   2-amino-6-fluoro-N-(3′-methyl-[4,4′-bipyridin]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    I-C-29);-   2-amino-6-fluoro-N-(4-methyl-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-30);-   2-amino-6-fluoro-N-(4-(3-methylpyridazin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-31);-   2-amino-6-fluoro-N-(2-hydroxy-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-32);-   2-amino-6-fluoro-N-(4-(4-methylpyridazin-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-33);-   2-amino-6-fluoro-N-(6-fluoro-2-methyl-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-34);-   2-amino-6-fluoro-N-(2-fluoro-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-35);-   2-amino-6-fluoro-N-(3-methyl-[2,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-36);-   2-amino-N-(2-chloro-[3,4′-bipyridin]-3′-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-37);-   2-amino-6-fluoro-N-(5-fluoro-1′-(1-methylpiperidine-4-carbonyl)-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-38);-   2-amino-6-fluoro-N-(2-methyl-6-(4-methylpiperazine-1-carbonyl)-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-39);-   2-amino-6-fluoro-N-(2-methyl-6-(4-methylpiperazin-1-yl)-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-40);-   (R)-2-amino-6-fluoro-N-(2-methyl-6-((1-methylpyrrolidin-3-yl)oxy)-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-41);-   2-amino-N-(4-cyclopropylpyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-42);-   2-amino-6-fluoro-N-(5-fluoro-4-(4-(4-methylpiperazine-1-carbonyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-43);-   2-amino-6-fluoro-N-(4-(4-(piperazine-1-carbonyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-44);-   2-amino-6-fluoro-N-(4-(2-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-45);-   2-amino-N-(3-chloro-5-(4-methylpiperazine-1-carbonyl)-[2,4′-bipyridin]-3′-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-46); and-   2-amino-N-(4-(1-(cyclopropylsulfonyl)piperidin-4-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-47);-   N-(4-(4-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)phenyl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-48);-   2-amino-6-fluoro-N-(4-(4-(4-(oxetan-3-yl)piperazine-1-carbonyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-49);-   N-(4-(4-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl)-2-fluorophenyl)pyridin-3-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-50);-   2-amino-6-fluoro-N-(4-(2-fluoro-4-(4-(oxetan-3-yl)piperazine-1-carbonyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-51);-   2-amino-6-fluoro-N-(6-(4-(oxetan-3-yl)piperazine-1-carbonyl)-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-52);-   2-amino-6-fluoro-N-(6-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-53);-   2-amino-N-(6-(4-(azetidin-1-yl)piperidine-1-carbonyl)-[3,4′-bipyridin]-3′-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-54);-   2-amino-6-fluoro-N-(4-(1-methyl-1H-imidazol-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-55);-   2-amino-6-fluoro-N-(4-(1-methyl-1H-imidazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-56);-   2-amino-6-fluoro-N-(4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-57);-   2-amino-6-fluoro-N-(1-methyl-6-oxo-1,6-dihydro-[2,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-58);-   2-amino-6-fluoro-N-(1-methyl-6-oxo-1,6-dihydro-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-59);-   N-([2,4′-bipyridin]-3′-yl)-2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-60);-   2-amino-6-fluoro-N-(4-(4-(methylsulfonyl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-61);-   2-amino-6-fluoro-N-(4-(3-methylpyrazin-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-62);-   2-amino-N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-63);-   2-amino-N-(4-(4-(azetidin-1-ylsulfonyl)phenyl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-64);-   2-amino-6-fluoro-N-(4-(1-methyl-1H-1,2,4-triazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-65);-   (S)-2-amino-6-fluoro-N-(4-(4-(4-methylmorpholin-3-yl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-66);-   2-amino-6-fluoro-N-(4-(5-methylpyrimidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-67);-   2-amino-6-fluoro-N-(4-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-68);-   2-amino-6-fluoro-N-(4-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-72);-   2-amino-6-fluoro-N-(4-(1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-73);-   2-amino-6-fluoro-N-(4-(tetrahydrofuran-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-75);-   2-amino-6-fluoro-N-(4-((2-oxopyrrolidin-1-yl)methyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-76);-   2-amino-N-(4-(1,2-dimethyl-1H-imidazol-5-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-77);-   2-amino-N-(4-(1,4-dimethyl-1H-imidazol-5-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-78);-   2-amino-6-fluoro-N-(5-fluoro-4-(1-methyl-1H-imidazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-79);-   2-amino-N-(4-(1-ethyl-1H-imidazol-5-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-80);-   2-amino-6-fluoro-N-(5-methoxy-4-(1-methyl-1H-imidazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-81);-   2-amino-6-fluoro-N-(5′-methoxy-[3,4′-bipyridin]-3′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-82);-   2-amino-6-fluoro-N-(4-(1-(2-methoxyethyl)-1H-imidazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-83); and-   2-amino-N-(4-cyclopropyl-5-methoxypyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-84).

Example 152-amino-6-fluoro-N-(7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-C-8)

tert-butyl5-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylatewas dissolved in MeOH (8 mL). Acetic acid (91.88 mg, 87.01 μL, 1.530mmol), formaldehyde (37% solution in water, 99.33 mg, 91.13 μL, 1.224mmol) and NaBH(OAc)₃ (324.3 mg, 1.530 mmol) was sequentially added andthe mixture was stirred for 1 hour at RT. The reaction mixture waspartitioned between an aqueous saturated solution of NaHCO₃ and DCM. Theinsoluble was filtered off and the combined organic extract was driedand concentrated in vacuo. The insoluble and the residue were combinedand purified by fractionlynx to yield2-amino-6-fluoro-N-(7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.MS (ES+) 342.2.

Example 165-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine2-oxide (Compound I-C-9)

To2-amino-6-fluoro-N-(7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(12 mg, 0.03516 mmol) in DCM (2 mL) was added mCPBA (5.764 mg, 0.03340mmol) and the mixture was stirred at RT for 2 h before the solvent wasremoved in vacuo. The residue was purified by FractionLynx to yield5-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-2-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine2-oxide. MS (ES+) 358.2.

Example 172-amino-6-fluoro-N-(4-(1-(1-methylpiperidine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-C-16)

Step 1:2-amino-6-fluoro-N-(4-(piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl4-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-4-pyridyl]piperidine-1-carboxylate(555 mg, 1.218 mmol) (prepared using a procedure similar to example 2)in MeOH (2.135 mL) and DCM (2.135 mL) was added TFA (6.2 g, 4.2 mL, 54mmol) and the resulting solution stirred at rt for 96 h. The reactionmixture was concentrated in vacuo and taken up in methanol and DCM andpassed through an 25 g SCX cartridge flushing with methanol (3 columnvolumes) followed by 2M ammonia in methanol (3 column volumes) to elutethe product. The filtrate was concentrated in vacuo to leave2-amino-6-fluoro-N-(4-(piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid that was used directly in the next step withoutfurther purification. MS (ES+) 356.1.

Step 2:2-amino-6-fluoro-N-(4-(1-(1-methylpiperidine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

TBTU (154.5 mg, 0.4812 mmol) and DIPEA (82.92 mg, 111.8 μL, 0.6416 mmol)were added to a solution of2-amino-6-fluoro-N-[4-(4-piperidyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(114 mg, 0.3208 mmol) and 1-methylpiperidine-4-carboxylic acid(Hydrochloric Acid (1)) (69.16 mg, 0.3850 mmol) in NMP (2.280 mL) andthe resulting solution stirred at RT for 2 h. Passed through an SCXcartridge flushing the desired product with 2M ammonia in methanol andthe filtrate concentrated in vacuo. The residue was purified byfractionlynx HPLC and the product fractions combined and freeze dried toleave2-amino-6-fluoro-N-(4-(1-(1-methylpiperidine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow crystalline solid. MS (ES+) 481.3.

The following compounds were formed using a procedure similar to Example17:

-   2-amino-6-fluoro-N-(4-(1-(4-methylpiperazine-1-carbonyl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-17); and-   2-amino-6-fluoro-N-(4-(1-(quinuclidine-4-carbonyl)piperidin-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Compound I-C-18).

Example 182-amino-6-fluoro-N-(1-methyl-1H-pyrrolo[2,3-a]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound I-C-74)

NaH (3.958 mg, 0.09894 mmol) was added to a suspension of2-amino-6-fluoro-N-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(28 mg, 0.08995 mmol) (synthesized according to a procedure similar toExample 1 or Example 3a) and MeI (11.49 mg, 5.039 μL, 0.08096 mmol) inDMF (3 mL) under N₂. The suspension was stirred at RT for 5 h beforewater (2 drops) was added. The crude mixture was purified byfractionlynx HPLC. Clean fractions were liophilized to yield2-amino-6-fluoro-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(5 mg, 16%). MS (ES+) 326.1.

Compound Analytical Data Cmpd LCMS LCMS No. ES+ (Rt min) HNMR I-C-1370.2 0.57 ¹H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.49 (dd, J = 4.7,2.5 Hz, 1H), 9.24 (s, 1H), 8.78 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 5.1Hz, 1H), 7.34 (d, J = 5.1 Hz, 1H), 6.71 (s, 2H), 2.93 (dt, J = 12.0, 2.9Hz, 2H), 2.81 (tq, J = 7.4, 3.8, 3.4 Hz, 1H), 2.23 (s, 3H), 2.04 (td, J= 11.7, 2.6 Hz, 2H), 1.82-1.66 (m, 4H). I-C-2 303.1 0.94 ¹H NMR (500MHz, DMSO-d6) δ 9.81 (s, 1H), 9.51 (s, 1H), 9.48 (d, J = 2.2 Hz, 1H),8.76 (d, J = 2.2 Hz, 1H), 8.44 (d, J = 5.4 Hz, 1H), 7.74 (d, J = 5.3 Hz,1H), 6.80 (s, 2H), 2.57 (s, 3H). I-C-3 308.1 0.58 — I-C-4 287.1 0.62 ¹HNMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.57 (s, 1H), 9.55 (dd, J = 4.8,2.5 Hz, 1H), 8.91 (dd, J = 2.6, 0.5 Hz, 1H), 8.48 (d, J = 5.5 Hz, 1H),7.91-7.73 (m, 1H), 6.77 (s, 2H), 2.61 (s, 3H). I-C-5 349.0 2.48* ¹H NMR(500 MHz, CDCl3) δ7.53-7.55 (2H, m), 7.67-7.73 (3H, m), 7.87 (1H, s),8.45-8.46 (1H, d), 7.61-8.62 (1H, d), 9.96 91H, s), 10.28 (1H, s). I-C-6370.0 0.74 ¹H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.64 (s, 1H),8.97-8.93 (m, 1H), 8.38 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H),7.62-7.55 (m, 3H), 7.54-7.50 (m, 2H), 7.33 (dd, J = 4.8, 0.7 Hz, 1H),6.68 (s, 2H), 4.06 (s, 2H). I-C-7 328.1 0.49 ¹H NMR (500 MHz, DMSO-d6) δ9.56 (s, 1H), 9.53 (dd, J = 4.8, 2.6 Hz, 1H), 9.24 (s, 1H), 9.16 (s,2H), 8.85 (dd, J = 2.6, 0.5 Hz, 1H), 8.30 (s, 1H), 6.73 (s, 2H),4.49-4.34 (m, 2H), 3.57-3.49 (m, 2H), 3.04 (t, J = 6.2 Hz, 2H). I-C-8342.2 0.58 ¹H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.59-9.47 (m, 2H),9.24 (s, 1H), 8.83 (dd, J = 2.6, 0.5 Hz, 1H), 8.26 (s, 1H), 6.73 (s,2H), 4.74-4.58 (m, 1H), 4.45-4.32 (m, 1H), 3.91-3.71 (m, 1H), 3.51-3.37(m, 1H), 3.24-3.12 (m, 1H), 3.12-3.03 (m, 1H), 3.00 (s, 3H). I-C-9 358.20.38 ¹H NMR (500 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.50 (dd, J = 4.8, 2.5Hz, 1H), 9.24 (s, 1H), 8.82 (d, J = 2.5 Hz, 1H), 8.10 (s, 1H), 6.75-6.67(m, 3H), 4.77 (d, J = 14.9 Hz, 1H), 4.36 (d, J = 14.9 Hz, 1H), 3.73 (td,J = 11.5, 5.1 Hz, 1H), 3.61-3.49 (m, 1H), 3.25-3.15 (m, 1H), 3.02-2.90(m, 1H). Methyl singlet hidden under water peak. I-C-10 412.2 1.78* ¹HNMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.62 (s, 1H), 9.55 (dd, J = 4.8,2.5 Hz, 1H), 9.32 (s, 1H), 8.94 (d, J = 2.5 Hz, 1H), 8.46 (d, J = 5.2Hz, 1H), 7.44 (d, J = 5.1 Hz, 1H), 6.75 (s, 2H), 4.89-4.71 (m, 4H), 4.51(s, 1H), 3.59 (d, J = 11.8 Hz, 2H), 3.37-3.09 (m, 1H), 3.08-2.84 (m,2H), 2.17 (d, J = 14.0 Hz, 2H), 1.97 (q, J = 13.2 Hz, 2H). I-C-11 428.11.95* ¹H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.53 (s, 1H), 9.48 (d,J = 2.2 Hz, 1H), 9.27 (s, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.44 (d, J =5.2 Hz, 1H), 7.39 (d, J = 6.1 Hz, 1H), 6.78 (s, 2H), 4.79 (p, J = 8.0Hz, 4H), 4.51 (s, 1H), 3.59 (s, 2H), 3.27-3.15 (m, 1H), 2.98 (d, J =15.4 Hz, 2H), 2.16 (d, J = 14.0 Hz, 2H), 1.95 (q, J = 10.6, 8.2 Hz, 2H).I-C-12 428.2 1.99* ¹H NMR (500 MHz, DMSO-d6) δ 9.56-9.52 (m, 2H), 9.45(s, 1H), 8.93 (d, J = 2.5 Hz, 1H), 8.39 (s, 1H), 6.78 (s, 1H), 6.16 (s,2H), 4.79 (s, 4H), 4.40-3.35 (very broad m, 7H). I-C-13 430.2 1.82* ¹HNMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.51 (dd, J = 4.8, 2.5 Hz, 1H),9.03 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 6.71(s, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.52-3.43(m, 1H), 3.09-2.91 (m, 1H), 2.86 (d, J = 10.9 Hz, 2H), 2.11 (q, J =13.0, 12.4 Hz, 2H), 1.85 (t, J = 11.5 Hz, 2H), 1.77 (d, J = 12.3 Hz,2H). I-C-14 388.2 1.82* ¹H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.53(dd, J = 4.7, 2.5 Hz, 1H), 9.41 (s, 1H), 8.91 (d, J = 2.6 Hz, 1H), 8.86(s, 1H), 8.40 (d, J = 2.3 Hz, 1H), 6.71 (s, 2H), 3.56 (d, J = 13.0 Hz,2H), 3.16 (t, J = 12.2 Hz, 1H), 3.03 (q, J = 12.0, 11.5 Hz, 2H), 2.82(d, J = 4.6 Hz, 3H), 2.26 (q, J = 13.8, 12.8 Hz, 2H), 2.08 (d, J = 13.7Hz, 2H). I-C-15 350.0 1.84* ¹H NMR (500 MHz, DMSO-d6) δ 6.8 (2H, br s),7.68-7.69 (1H, d), 7.75-7.77 (1H, dd), 8.14-8.16 (1H, dd), 8.21-8.22(1H, d), 8.56-8.57 (1H, dd), 8.82-8.83 (1H, d), 8.87-8.88 1H, d),9.41-9.42 (1H, d), 9.67 (1H, s), 9.77 (1H, s). I-C-16 481.3 1.80* ¹H NMR(DMSO-d6, 500 MHz) δ 1.42-1.65 (6H, m), 1.91 (2H, m), 2.10 (1H, m), 2.29(3H, br s), 2.64-2.71 (2H, m), 2.89 (2H, m), 3.12-3.21 (3H, m), 4.09(1H, m), 4.63 (1H, m), 6.72 (2H, br s), 7.34 (1H, d, J = 5 Hz), 8.29(1H, d, J = 5 Hz), 8.93 (1H, m), 9.28 (1H, s), 9.51 (1H, dd) and 9.62(1H, s) ppm. I-C-17 482.2 1.85* ¹H NMR (500 MHz, DMSO-d6) δ 1.67-1.75(2H, m), 1.87 (2H, m), 2.85 (3H, s), 3.01-3.22 (7H, m), 3.41 (2H, m),3.69 (2H, m), 3.86 (2H, m), 6.77 (2H, br s), 7.65 (1H, d, J = 5 Hz),8.47 (1H, d), 8.95 (1H, d), 9.49 (1H, s), 9.55 (1H, m), 9.83 (1H, s) and9.95 (1H, br s) ppm. I-C-18 493.2 1.69* ¹H NMR (500 MHz, DMSO-d6) δ1.50-1.59 (2H, m), 1.73 (6H, m), 1.87 (2H, m), 2.76 (6H, m), 2.93 (2H,m), 3.15 (1H, m), 4.61 (2H, m), 6.72 (2H, br s), 7.34 (1H, d), 8.29 (1H,d), 8.93 (1H, d), 9.26 (1H, s), 9.50 (1H, dd) and 9.62 (1H, s) ppm.I-C-19 476.0 1.74* ¹H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.70 (s,1H), 9.53 (s, 1H), 9.42 (dd, J = 4.8, 2.5 Hz, 1H), 8.75 (dd, J = 2.2,0.9 Hz, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.36-8.32 (m, 1H), 8.22 (dd, J =8.0, 2.2 Hz, 1H), 7.90 (dd, J = 8.0, 0.9 Hz, 1H), 7.48 (dd, J = 4.9, 0.7Hz, 1H), 6.70 (m, 2H), 4.68 (m, 1H), 4.07 (m, 1H), 3.59 (m, 1H), 3.44(m, 2H), 3.16 (m, 3H), 2.87 (s, 3H). I-C-20 364.0 1.92* ¹H NMR (500 MHz,DMSO-d6) δ 9.80 (s, 0H), 9.42 (dd, J = 4.8, 2.5 Hz, 0H), 9.35 (s, 0H),8.86 (dd, J = 5.2, 1.6 Hz, 0H), 8.57 (d, J = 5.1 Hz, 0H), 8.07 (d, J =2.5 Hz, 0H), 7.99 (d, J = 7.5 Hz, 0H), 7.68 (dd, J = 7.7, 5.2 Hz, 0H),7.63 (d, J = 5.1 Hz, 0H), 2.35 (s, 1H). I-C-21 448.0 1.94* ¹H NMR (500MHz, DMSO-d6) δ 10.15 (s, 1H), 9.90 (s, 1H), 9.67 (s, 1H), 9.47 (dd, J =4.8, 2.5 Hz, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8.42 (dd, J = 2.5, 0.7 Hz,1H), 8.30 (d, J = 2.5 Hz, 1H), 7.94 (dd, J = 8.8, 2.5 Hz, 1H), 7.69 (d,J = 5.4 Hz, 1H), 7.21 (dd, J = 9.0, 0.9 Hz, 1H), 4.60 (s, 2H), 3.59 (s,2H), 3.28 (s, 2H), 3.13 (s, 2H), 2.89 (s, 3H). I-C-22 364.0 1.97* ¹H NMR(500 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.68 (s, 1H), 9.44 (dd, J = 4.8, 2.5Hz, 1H), 8.81 (dd, J = 2.4, 0.9 Hz, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.25(d, J = 2.5 Hz, 1H), 8.21 (dd, J = 8.1, 2.3 Hz, 1H), 7.76-7.72 (m, 1H),7.69 (dd, J = 5.2, 0.6 Hz, 1H), 2.72 (s, 3H). I-C-23 419.1 2.01* ¹H NMR(500 MHz, DMSO-d6) δ 1.86 (6H, s), 1.90-2.00 (2H, br m), 2.07 (2H, d),2.79 (3H, s), 3.0-3.1 (1H, m), 3.52 (2H, br s), 6.63 (2H, s), 7.32 (1H,s), 8.40 (1H, d), 8.81 (1H, d), 9.09 (2H, d), 9.51 (1H, s). I-C-24 350.01.80* ¹H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.58 (s, 1H), 9.43 (dd,J = 4.8, 2.5 Hz, 1H), 8.91-8.86 (m, 2H), 8.54 (d, J = 5.1 Hz, 1H), 8.25(d, J = 2.5 Hz, 1H), 7.77-7.72 (m, 2H), 7.59 (d, J = 5.0 Hz, 1H). I-C-25475.0 1.99* ¹H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.80 (s, 1H),9.66 (s, 1H), 9.40 (dd, J = 4.8, 2.5 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H),8.36 (d, J = 2.5 Hz, 1H), 7.75-7.69 (m, 2H), 7.68-7.63 (m, 2H), 7.56 (d,J = 5.0 Hz, 1H), 6.72 (s, 2H), 4.65 (s, 2H), 3.0 to 4.0 (m, 6H), 2.86(s, 3H). I-C-26 351.0 1.47* ¹H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H),9.49 (s, 1H), 9.48 (dd, J = 5.3, 1.3 Hz, 1H), 9.44 (dd, J = 2.4, 1.2 Hz,1H), 9.42 (dd, J = 4.8, 2.5 Hz, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.26 (d,J = 2.5 Hz, 1H), 7.98 (dd, J = 5.3, 2.4 Hz, 1H), 7.52 (dd, J = 5.0, 0.7Hz, 1H), 6.66 (s, 1H). I-C-27 380.0 2.23* ¹H NMR (500 MHz, DMSO-d6) δ9.78 (s, 1H), 9.69 (s, 1H), 9.45 (dd, J = 4.8, 2.5 Hz, 1H), 8.55 (d, J =5.3 Hz, 1H), 8.41 (dd, J = 2.6, 0.8 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H),7.98 (dd, J = 8.6, 2.5 Hz, 1H), 7.69 (dd, J = 5.2, 0.6 Hz, 1H), 7.12(dd, J = 8.6, 0.8 Hz, 1H), 3.99 (s, 3H). I-C-28 351.0 1.58* ¹H NMR (500MHz, DMSO-d6) δ 9.54 (s, 1H), 9.42 (dd, J = 4.8, 2.5 Hz, 1H), 9.40 (s,1H), 9.05 (s, 2H), 8.26 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 4.7 Hz, 1H),6.68 (s, 2H). I-C-29 364.0 1.95* ¹H NMR (500 MHz, DMSO-d6) δ 9.75 (s,1H), 9.41 (dd, J = 4.8, 2.5 Hz, 1H), 9.22 (s, 1H), 8.80 (s, 1H), 8.71(d, J = 5.0 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H),7.50-7.44 (m, 2H), 6.70 (bs, 1h), 2.12 (s, 3H). I-C-30 364.0 1.97* ¹HNMR (500 MHz, DMSO-d6) δ 9.80 (d, J = 0.7 Hz, 1H), 9.41 (dd, J = 4.8,2.5 Hz, 1H), 9.29 (s, 1H), 8.79 (d, J = 5.3 Hz, 1H), 8.59 (s, 1H), 8.52(d, J = 5.0 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.75-7.68 (m, 1H), 7.54(dd, J = 5.1, 0.7 Hz, 1H), 6.71 (s, 2H), 2.19 (d, J = 0.7 Hz, 3H).I-C-31 365.0 1.58* ¹H NMR (500 MHz, DMSO-d6) δ 9.73 (d, J = 0.6 Hz, 1H),9.41 (dd, J = 4.8, 2.5 Hz, 1H), 9.38 (d, J = 5.0 Hz, 1H), 9.21 (s, 1H),8.53 (d, J = 5.0 Hz, 1H), 2.45 (s, 3H). I-C-32 366.0 1.53* ¹H NMR (500MHz, DMSO-d6) δ 12.15 (s, 1H), 9.61 (s, 1H), 9.52 (s, 1H), 9.43 (dd, J =4.8, 2.6 Hz, 1H), 8.46 (s, 1H), 8.42 (d, J = 5.0 Hz, 1H), 7.78-7.60 (m,2H), 7.45 (d, J = 5.1 Hz, 1H), 6.70 (s, 2H), 6.43 (t, J = 6.6 Hz, 1H).I-C-33 365.0 1.58* ¹H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.59 (s,1H), 9.40 (dd, J = 4.8, 2.5 Hz, 1H), 9.37 (d, J = 5.3 Hz, 1H), 8.56 (d,J = 5.0 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.87 (dd, J = 5.1, 1.0 Hz,1H), 7.71-7.62 (m, 1H), 2.21 (d, J = 0.8 Hz, 3H). I-C-34 382.0 2.24* ¹HNMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.44 (dd, J = 4.8, 2.5 Hz, 1H),9.35 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.98(t, J = 8.2 Hz, 1H), 7.57 (d, J = 5.1 Hz, 1H), 7.33-7.26 (m, 1H), 2.23(s, 3H). I-C-35 368.0 2.03* ¹H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H),9.47 (s, 1H), 9.43 (dd, J = 4.8, 2.5 Hz, 1H), 8.55 (ddd, J = 4.9, 1.9,1.0 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.19 (ddd, J = 9.6, 7.4, 2.0 Hz,1H), 8.15 (d, J = 2.5 Hz, 1H), 7.65 (ddd, J = 7.1, 4.9, 1.9 Hz, 1H),7.59 (d, J = 5.0 Hz, 1H). I-C-36 364.0 2.03* ¹H NMR (500 MHz, DMSO-d6) δ9.94 (s, 1H), 9.78 (s, 1H), 9.40 (dd, J = 4.8, 2.5 Hz, 1H), 8.77 (ddd, J= 4.8, 1.7, 0.8 Hz, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.36 (d, J = 2.5 Hz,1H), 7.95 (ddd, J = 7.8, 1.6, 0.8 Hz, 1H), 7.71 (d, J = 5.1 Hz, 1H),7.60 (dd, J = 7.8, 4.8 Hz, 1H), 2.22 (s, 3H). I-C-37 384.0 2.08* ¹H NMR(500 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.42 (dd, J = 4.8, 2.5 Hz, 1H), 9.34(s, 1H), 8.74 (dd, J = 4.8, 1.9 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H),8.07-8.00 (m, 2H), 7.72 (dd, J = 7.5, 4.8 Hz, 1H), 7.55 (d, J = 5.0 Hz,1H). I-C-38 497.2 2.02* ¹H NMR (500 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.46(s, 1H), 9.32 (dd, J = 4.7, 2.5 Hz, 1H), 8.61 (s, 1H), 8.31 (s, 1H),6.08 (dt, J = 3.3, 1.9 Hz, 1H), 4.29 (q, J = 2.9 Hz, 2H), 3.82 (t, J =5.6 Hz, 2H), 3.49 (s, 1H), 3.01 (s, 3H), 2.80 (s, 3H), 2.44 (d, J = 6.3Hz, 3H), 1.90 (s, 4H). I-C-39 490.0 1.89* ¹H NMR (500 MHz, DMSO-d6) δ10.13 (s, 1H), 9.86 (s, 1H), 9.39 (dd, J = 4.8, 2.5 Hz, 1H), 9.31 (s,1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.72 (d, J =7.7 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 6.72 (s, 2H), 4.70 (s, 1H), 4.02(s, 1H), 3.33 (d, J = 118.2 Hz, 5H), 2.87 (s, 3H), 2.28 (s, 3H). I-C-40462.0 2.33* ¹H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.47 (s, 1H), 9.40(dd, J = 4.8, 2.5 Hz, 1H), 8.35 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 2.5Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 4.8, 0.7 Hz, 1H), 6.84(d, J = 8.4 Hz, 1H), 6.70 (s, 2H), 3.63 (d, J = 33.6 Hz, 4H), 2.47 (s,4H), 2.28 (s, 3H), 2.08 (s, 3H). I-C-41 463.0 2.35* ¹H NMR (500 MHz,DMSO-d6) δ 9.68 (s, 1H), 9.41 (dd, J = 4.8, 2.5 Hz, 1H), 9.32 (s, 1H),8.38 (d, J = 4.8 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.59 (d, J = 8.3 Hz,1H), 7.31 (dd, J = 4.8, 0.7 Hz, 1H), 6.85 (dd, J = 8.4, 0.8 Hz, 1H),6.71 (s, 2H), 2.86 (dd, J = 10.5, 6.1 Hz, 1H), 2.73 (td, J = 8.2, 5.7Hz, 1H), 2.69-2.62 (m, 1H), 2.41 (td, J = 7.9, 6.1 Hz, 1H), 2.37-2.31(m, 0H), 2.29 (s, 3H), 2.15 (s, 3H), 1.93-1.83 (m, 1H). I-C-42 313.02.22* ¹H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.61 (s, 1H), 9.52 (dd,J = 4.7, 2.5 Hz, 1H), 8.92 (d, J = 2.5 Hz, 1H), 8.51-8.40 (m, 1H), 7.58(d, J = 5.6 Hz, 1H), 6.77 (s, 2H), 2.18 (tt, J = 8.4, 5.2 Hz, 1H),1.39-1.33 (m, 2H), 1.01-0.94 (m, 2H). I-C-43 493.0 2.22* ¹H NMR (500MHz, DMSO-d6) δ 9.64 (s, 1H), 9.39 (s, 1H), 9.22 (dd, J = 4.7, 2.5 Hz,1H), 8.42 (s, 1H), 8.35 (dd, J = 2.5, 0.6 Hz, 1H), 7.69-7.54 (m, 4H),6.49 (s, 2H), 3.66 (s, 4H), 2.74 (s, 4H), 2.48 (s, 3H). I-C-44 461.01.79* ¹H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.54 (s, 1H), 9.37 (dd,J = 4.8, 2.5 Hz, 1H), 8.41-8.38 (m, 2H), 7.59 (d, J = 8.4 Hz, 2H),7.57-7.53 (m, 2H), 7.37 (dd, J = 4.8, 0.7 Hz, 1H), 6.69 (s, 2H), 3.62(s, 2H), 2.73 (d, J = 55.4 Hz, 4H). I-C-45 489.0 2.16* ¹H NMR (500 MHz,DMSO-d6) δ 9.82 (s, 1H), 9.34 (dd, J = 4.8, 2.5 Hz, 1H), 9.27 (s, 1H),8.39 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 7.54-7.48 (m, 1H), 7.41 (dd, J =7.7, 1.6 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.30 (dd, J = 4.7, 0.7 Hz,1H), 6.68 (s, 2H), 3.73 (bs, 2H), 3.42 (bs, 2H), 2.45-2.30 (m, 4H), 2.08(s, 3H). I-C-46 510.0 2.00* ¹H NMR (500 MHz, DMSO-d6) δ 9.78 (d, J = 0.7Hz, 1H), 9.61 (s, 1H), 9.41 (dd, J = 4.8, 2.5 Hz, 1H), 8.93 (d, J = 1.8Hz, 1H), 8.53 (dd, J = 2.6, 0.6 Hz, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.36(d, J = 1.8 Hz, 1H), 7.53 (dd, J = 5.0, 0.7 Hz, 1H), 6.71 (s, 2H), 2.86(s, 3H). I-C-47 460.1 2.13* ¹H NMR (500 MHz, methanol-d4) δ 1.09-1.15(4H, m), 1.99 (2H, m), 2.15-2.17 (2H, m), 2.64-2.69 (1H, m), 3.17-3.19(2H, m), 3.31-3.34 (1H, masked), 4.03-4.06 (2H, m), 7.94-7.95 (1H, d),8.50-8.51 (1H, d), 8.78 (1H, dd), 9.13-9.14 (1H, dd), 9.74 (1H, s).I-C-48 501.0 2.01* ¹H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.77 (s,1H), 9.61 (s, 1H), 9.40 (dd, J = 4.8, 2.5 Hz, 1H), 8.46 (d, J = 4.9 Hz,1H), 8.41 (s, 1H), 7.71 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H),7.46 (d, J = 5.0 Hz, 1H), 6.72 (bs, 2H), 4.85 (s, 1H), 4.09 (s, 1H),3.77 (t, J = 5.6 Hz, 1H), 3.58 (s, 1H), 3.45 (s, 2H), 3.33 (s, 1H), 2.20(d, J = 69.6 Hz, 4H), 1.96 (s, 1H). I-C-49 517.0 1.93* ¹H NMR (500 MHz,DMSO-d6) δ 9.69 (s, 1H), 9.53 (s, 1H), 9.38 (dd, J = 4.8, 2.5 Hz, 1H),8.44-8.32 (m, 2H), 7.64-7.59 (m, 2H), 7.59-7.53 (m, 2H), 7.37 (dd, J =4.8, 0.7 Hz, 1H), 6.69 (s, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J =6.0 Hz, 2H), 3.73 (s, 2H), 3.47 (t, J = 6.2 Hz, 1H), 3.40 (d, J = 5.8Hz, 2H), 2.38 (d, J = 6.0 Hz, 2H), 2.27 (s, 2H). I-C-50 519.0 2.08* ¹HNMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.42 (s, 1H), 9.39 (dd, J = 4.8,2.5 Hz, 1H), 8.46-8.38 (m, 2H), 7.63-7.54 (m, 2H), 7.45 (dd, J = 7.8,1.5 Hz, 1H), 7.42 (dd, J = 4.8, 0.7 Hz, 1H), 6.70 (s, 2H), 4.57 (t, J =6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.73 (s, 2H), 3.49 (m, 2H), 3.39(m, 2H), 2.46-2.35 (m, 3H), 2.29 (m, 2H). I-C-51 535.0 2.00* ¹H NMR (500MHz, DMSO-d6) δ 9.73 (s, 1H), 9.42 (s, 1H), 9.39 (dd, J = 4.8, 2.5 Hz,1H), 8.46-8.39 (m, 2H), 7.62-7.55 (m, 2H), 7.48-7.40 (m, 2H), 6.70 (s,2H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 3.73 (s, 2H),3.49 (s, 1H), 3.39 (s, 2H), 2.40 (s, 2H), 2.29 (s, 2H). I-C-52 518.01.7* ¹H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.49 (s, 1H), 9.39 (dd, J= 4.8, 2.5 Hz, 1H), 8.71 (dd, J = 2.1, 0.8 Hz, 1H), 8.44 (d, J = 4.9 Hz,1H), 8.38 (d, J = 2.5 Hz, 1H), 8.13 (dd, J = 8.0, 2.2 Hz, 1H), 7.80 (dd,J = 8.0, 0.9 Hz, 1H), 7.45 (d, J = 4.9 Hz, 1H), 6.69 (s, 2H), 4.56 (t, J= 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 3.76 (s, 2H), 3.58-3.40 (m,3H), 2.42 (s, 2H), 2.29 (s, 2H). I-C-53 530.0 1.98* ¹H NMR (500 MHz,DMSO-d6) δ 9.68 (s, 1H), 9.50 (s, 1H), 9.40 (dd, J = 4.8, 2.5 Hz, 1H),8.70 (dd, J = 2.2, 0.9 Hz, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.41-8.40 (m,1H), 8.12 (dd, J = 8.0, 2.2 Hz, 1H), 7.78 (dd, J = 8.0, 0.9 Hz, 1H),7.45 (dd, J = 4.8, 0.7 Hz, 1H), 6.69 (s, 2H), 4.37 (d, J = 12.1 Hz, 1H),3.64 (d, J = 12.6 Hz, 1H), 3.18-3.03 (m, 2H), 2.56 (s, 4H), 2.37 (s,1H), 1.98 (d, J = 12.1 Hz, 1H), 1.80 (d, J = 10.1 Hz, 1H), 1.71 (d, J =6.2 Hz, 4H), 1.47 (td, J = 20.6, 17.0, 10.5 Hz, 2H). I-C-54 516.2 1.98*¹H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H), 10.33 (s, 1H), 9.68 (s, 1H),9.43 (dd, J = 4.8, 2.6 Hz, 1H), 8.96 (dd, J = 2.2, 0.9 Hz, 1H), 8.87 (d,J = 2.5 Hz, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.09 (dd, J = 8.1, 2.2 Hz,1H), 8.04 (dd, J = 8.1, 0.9 Hz, 1H), 7.85 (d, J = 5.2 Hz, 1H), 6.73 (s,2H), 4.60 (s, 1H), 4.16 (s, 2H), 4.06 (s, 2H), 3.69 (s, 1H), 3.55-3.38(m, 1H), 3.17 (d, J = 7.9 Hz, 1H), 2.90 (s, 1H), 2.45 (dt, J = 11.6, 9.3Hz, 1H), 2.24 (ddd, J = 12.4, 7.8, 4.6 Hz, 1H), 2.07 (d, J = 11.5 Hz,1H), 1.89 (s, 1H), 1.37 (s, 2H). I-C-55 353.0 1.66* ¹H NMR (500 MHz,DMSO-d6) δ 10.81 (s, 1H), 9.72 (d, J = 0.6 Hz, 1H), 9.40 (dd, J = 4.9,2.6 Hz, 1H), 8.67 (d, J = 2.6 Hz, 1H), 8.42 (d, J = 4.9 Hz, 1H), 7.59(dd, J = 5.0, 0.7 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 1.2Hz, 1H), 6.71 (s, 2H), 3.72 (s, 3H). I-C-56 353.0 1.66* ¹H NMR (500 MHz,DMSO-d6) δ 9.86-9.70 (m, 1H), 9.35-9.28 (m, 1H), 8.52 (d, J = 4.9 Hz,1H), 8.50 (dd, J = 2.5, 0.5 Hz, 1H), 8.08 (d, J = 1.5 Hz, 1H), 7.60 (dd,J = 5.0, 0.7 Hz, 1H), 3.69 (d, J = 0.6 Hz, 3H). I-C-57 353.1 1.88* ¹HNMR (500 MHz, DMSO-d6) δ 3.65 (3H, s), 6.55 (1H, d), 6.71 (2H, br s),7.44 (1H, m), 7.75 (1H, m), 8.35 (1H, m), 8.42 (1H, m), 9.41 (1H, m),9.56 (1H, s) and 9.77 (1H, s) ppm. I-C-58 380.0 1.67* ¹H NMR (500 MHz,DMSO-d6) δ 3.16 (3H, s), 6.34 (1H, m), 6.70 (1H, m), 7.53 (1H, m),7.59-7.62 (1H, m), 8.24 (1H, m), 8.49 (1H, d), 9.39 (1H, s), 9.45 (1H,m) and 9.79 (1H, s) ppm. I-C-59 380.1 1.52* ¹H NMR (500 MHz, DMSO-d6) δ3.47 (3H, s), 6.57 (1H, m), 6.72 (2H, br s), 7.36 (1H, m), 7.58 (1H, m),8.06 (1H, m), 8.26 (1H, m), 8.36 (1H, m), 9.44 (1H, m) and 9.52 (1H, s)ppm. I-C-60 350.0 1.98* ¹H NMR (500 MHz, DMSO-d6) δ 6.73 (2H, br s),7.54 (1H, m), 7.72 (1H, m), 7.96 (1H, m), 8.04 (1H, m), 8.42 (1H, m),8.89 (1H, m), 9.40 (1H, m), 9.58 (1H, s) and 11.85 (1H, s) ppm. I-C-61427.0 1.98* ¹H NMR (500 MHz, DMSO-d6) δ 3.37 (3H, s), 6.70 (2H, br s),7.40 (1H, m), 7.81 (2H, m), 8.14-8.17 (2H, m), 8.43 (1H, m), 9.39 (1H,m), 9.47 (1H, s) and 9.64 (1H, s) ppm. I-C-62 365.0 1.74* ¹H NMR (500MHz, DMSO-d6) δ 9.92 (s, 1H), 9.83 (s, 1H), 9.43 (dd, J = 4.8, 2.5 Hz,1H), 8.88 (dd, J = 2.5, 0.8 Hz, 1H), 8.86 (d, J = 2.5 Hz, 1H), 8.66 (d,J = 5.4 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 5.3 Hz, 1H),6.67 (s, 2H), 2.46 (d, J = 0.7 Hz, 3H). I-C-63 367.8 1.83* ¹H NMR (500MHz, DMSO-d6) δ 2.06 (3H, s), 3.88 (3H, s), 6.72 (2H, br s), 7.27 (1H,m), 7.91 (1H, s), 8.30 (1H, m), 8.37 (1H, m), 9.42 (1H, m) and 9.59 (2H,m) ppm. I-C-64 468.0 2.29* ¹H NMR (500 MHz, DMSO-d6) δ 2.02-2.08 (2H,m), 3.78 (4H, m), 6.69 (2H, br s), 7.44 (1H, m), 7.82 (2H, m), 8.01 (2H,m), 8.21 (1H, m), 8.44 (1H, m), 9.40 (1H, m), 9.48 (1H, s) and 9.57 (1H,s) ppm. I-C-65 354.0 1.51* ¹H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H),9.82 (d, J = 0.7 Hz, 1H), 9.43 (dd, J = 4.9, 2.5 Hz, 1H), 8.67 (d, J =2.5 Hz, 1H), 8.55 (d, J = 5.1 Hz, 1H), 8.44 (s, 1H), 7.84-7.79 (m, 1H),6.75 (s, 1H), 3.91 (s, 3H). I-C-66 448.1 2.26* ¹H NMR (500 MHz, DMSO-d6)δ 9.59 (s, 1H), 9.52 (s, 1H), 9.40 (dd, J = 4.8, 2.5 Hz, 1H), 8.37 (d, J= 4.8 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H), 7.58-7.53 (m, 2H), 7.49 (d, J =8.2 Hz, 2H), 7.34 (dd, J = 4.8, 0.7 Hz, 1H), 6.70 (s, 2H), 3.90-3.80 (m,1H), 3.72-3.62 (m, 2H), 3.17 (dd, J = 10.2, 3.3 Hz, 1H), 2.85 (dt, J =11.8, 1.9 Hz, 1H), 2.32 (td, J = 11.7, 3.4 Hz, 1H), 1.98 (d, J = 11.0Hz, 3H). I-C-67 365.1 1.69* ¹H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H),9.76 (s, 1H), 9.46-9.39 (m, 2H), 9.00 (d, J = 0.9 Hz, 1H), 8.61 (d, J =5.2 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 5.2 Hz, 1H), 6.68(s, 2H), 2.23 (t, J = 0.7 Hz, 3H). I-C-68 353.1 1.93* 1H NMR (500 MHz,DMSO-d6) δ 11.31 (s, 1H), 9.49-9.36 (m, 2H), 8.86 (d, J = 2.6 Hz, 1H),8.32 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 5.1 Hz,1H), 6.93 (d, J = 2.3 Hz, 1H), 6.74 (s, 2H), 3.92 (s, 3H). I-C-69 398.01.76* ¹H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.53-9.55 (m, 2H), 8.99(dd, 1H), 8.50 (d, 1H), 7.71-7.73 (d, 1H), 6.80 3(s, 2H), 4.63-4.66 (m,1H), 4.03-4.05 (m, 1H), 3.25-3.28 (m, 2H), 2.70-2.75 (m, 1H), 2.06 (s,3H), 1.85-1.95 (m, 2H), 1.75-1.80 (m, 1H), 1.55-1.60 (m, 1H). I-C-70424.0 2.04* ¹H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.53-9.55 (m, 2H),9.00 (dd, 1H), 8.50 (dd, 1H), 7.73-7.74 (d, 1H), 6.80 3(s, 2H),4.65-4.70 (m, 1H), 4.50-4.55 (m, 1H), 3.25-3.33 (m, 2H), 2.85-2.88 (m,1H), 1.85-2.06 (m, 3H), 1.55-1.80 (m, 2H), 0.71-0.77 (m, 4H). I-C-71449.0 2.07* — I-C-72 354.1 1.61* ¹H NMR (500 MHz, DMSO-d6) δ 9.72 (d, J= 0.7 Hz, 1H), 9.48 (s, 1H), 9.45 (dd, J = 4.8, 2.6 Hz, 1H), 8.49 (d, J= 4.9 Hz, 1H), 8.24 (d, J = 2.5 Hz, 1H), 8.06 (s, 1H), 7.56 (dd, J =4.9, 0.7 Hz, 1H), 6.71 (s, 2H), 3.91 (s, 3H). I-C-73 384.1 1.58* ¹H NMR(500 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.53 (dd, J = 4.8, 2.5 Hz, 1H), 9.34(s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.58 (d, J= 5.2 Hz, 1H), 6.73 (s, 2H), 3.38 (dt, J = 12.4, 4.5 Hz, 2H), 2.91 (s,3H), 2.70-2.62 (m, 1H), 2.49-2.45 (m, 1H), 2.15-2.08 (m, 2H). I-C-74326.1 1.97* ¹H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.51-9.52 (dd,1H), 9.11 (s, 1H), 9.00 (dd, 1H), 8.70 (s, 1H), 7.70 (s, 1H), 6.74-6.75(m, 3H), 3.97 (s, 3H). I-C-75 343.1 1.81* ¹H NMR (500 MHz, DMSO-d6) δ9.87 (s, 1H), 9.53 (dd, 1H), 9.39 (s, 1H), 8.91 (dd, 1H), 8.48 (d, 1H),7.68 (d, 1H), 6.74 (s, 2H), 4.09 (dd, 1H), 3.97-3.88 (m, 3H), 3.81-3.76(m, 1H), 2.61-2.53 (m, 1H), 2.04-1.97 (m, 1H). I-C-76 370.0 1.53* run inD6-DMSO I-C-77 367.1 1.68* ¹H NMR (500 MHz, DMSO) δ 15.03 (s, 1H), 9.76(d, J = 0.7 Hz, 1H), 9.52-9.46 (m, 2H), 8.55 (d, J = 2.5 Hz, 1H), 8.51(d, J = 4.8 Hz, 1H), 8.02 (s, 1H), 7.52 (dd, J = 4.9, 0.7 Hz, 1H), 6.75(s, 2H), 3.49 (s, 3H), 2.72 (s, 3H). I-C-78 367.1 1.71* ¹H NMR (500 MHz,DMSO) δ? 9.80 (d, J = 0.7 Hz, 1H), 9.56 (s, 1H), 9.42 (dd, J = 4.8, 2.6Hz, 1H), 8.40 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.91 (s,1H), 7.39 (dd, J = 4.8, 0.7 Hz, 1H), 6.71 (s, 2H), 3.40 (s, 3H), 1.97(s, 3H). I-C-79 371.0 1.84* ¹H NMR (500 MHz, DMSO-d6) 9.70 (s, 2H),09.44 (dd, 1H), 8.47 (s, 1H), 8.32 (d, 1H), 8.08 (dd, 1H), 7.26 (d, 1H),6.79-6.64 (m, 2H), 3.47 (s, 3H). I-C-80 367.1 1.76* ¹H NMR (500 MHz,DMSO-d6) 9.76 (s, 1H), 9.59 (s, 1H), 9.41-9.43 (m, 1H), 8.40 (d, 1H),8.33 (d, 1H), 8.07 (d, 1H), 7.40 (m, 1H), 7.13 (d, 1H), 6.71 (s, 2H),3.79-3.83 (qd, 2H), 1.09-1.12 (t, 3H). I-C-81 383.1 1.7* ¹H NMR (500MHz, Methanol-d4) 3.90 (d, 1H), 9.08 (s, 1H), 8.91 (d, 1H), 8.30 (s,1H), 8.24 (s, 1H), 7.78 (s, 1H), 3.91 (s, 3H), 3.65 (s, 3H). I-C-82380.1 1.92* ¹H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H0, 9.39-9.40 (d, 1H),9.32 (s, 1H), 8.87-8.89 (d, 1H), 8.69 (dd, 1H), 8.41 (s, 1H), 8.08 (d,1H0, 8.02-8.05 (m, 1H0, 7.78-7.80 (m, 1H0, 6.80 (br s, 2H), 3.89 (s,3H). I-C-83 397.1 1.69* ¹H NMR (500 MHz, CDCl3) δ 9.95 (s, 1H), 9.60 (s,1H), 8.53 (m, 1H0, 8.47-8.48 (m, 1H), 8.43-8.44 (m, 1H), 8.38 (m, 1H),7.93 (s, 1H), 7.20-7.30 (masked, 2H), 5.73 (s, 2H), 3.91-3.93 (t, 2H),3.40-3.42 (t, 2H), 3.14 (s, 3H). I-C-84 343.1 2.3* — Retention timesmeasured using HPLC Method B, described in the Experimental Methods andMaterials section, above., are designated by (*). For all othercompounds, the retention time was measured using the HPLC Method A.

Example 19 Cellular ATR Inhibition Assay

Compounds can be screened for their ability to inhibit intracellular ATRusing an immunofluorescence microscopy assay to detect phosphorylationof the ATR substrate histone H2AX in hydroxyurea treated cells. HT29cells are plated at 14,000 cells per well in 96-well black imagingplates (BD 353219) in McCoy's 5A media (Sigma M8403) supplemented with10% foetal bovine serum (JRH Biosciences 12003), Penicillin/Streptomycinsolution diluted 1:100 (Sigma P7539), and 2 mM L-glumtamine (SigmaG7513), and allowed to adhere overnight at 37° C. in 5% CO₂. Compoundsare then added to the cell media from a final concentration of 25 μM in3-fold serial dilutions and the cells are incubated at 37° C. in 5% CO₂.After 15 min, hydroxyurea (Sigma H8627) is added to a finalconcentration of 2 mM.

After 45 min of treatment with hydroxyurea, the cells are washed in PBS,fixed for 10 min in 4% formaldehyde diluted in PBS (Polysciences Inc18814), washed in 0.2% Tween-20 in PBS (wash buffer), and permeabilisedfor 10 min in 0.5% Triton X-100 in PBS, all at room temperature. Thecells are then washed once in wash buffer and blocked for 30 min at roomtemperature in 10% goat serum (Sigma G9023) diluted in wash buffer(block buffer). To detect H2AX phosphorylation levels, the cells arethen incubated for 1 h at room temperature in primary antibody (mousemonoclonal anti-phosphorylated histone H2AX Ser139 antibody; Upstate05-636) diluted 1:250 in block buffer. The cells are then washed fivetimes in wash buffer before incubation for 1 h at room temperature inthe dark in a mixture of secondary antibody (goat anti-mouse Alexa Fluor488 conjugated antibody; Invitrogen A11029) and Hoechst stain(Invitrogen H3570); diluted 1:500 and 1:5000, respectively, in washbuffer. The cells are then washed five times in wash buffer and finally100 ul PBS is added to each well before imaging.

Cells are imaged for Alexa Fluor 488 and Hoechst intensity using the BDPathway 855 Bioimager and Attovision software (BD Biosciences, Version1.6/855) to quantify phosphorylated H2AX Ser139 and DNA staining,respectively. The percentage of phosphorylated H2AX-positive nuclei in amontage of 9 images at 20× magnification is then calculated for eachwell using BD Image Data Explorer software (BD Biosciences Version2.2.15). Phosphorylated H2AX-positive nuclei are defined asHoechst-positive regions of interest containing Alexa Fluor 488intensity at 1.75-fold the average Alexa Fluor 488 intensity in cellsnot treated with hydroxyurea. The percentage of H2AX positive nuclei isfinally plotted against concentration for each compound and IC50s forintracellular ATR inhibition are determined using Prism software(GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, SanDiego Calif., USA).

The compounds described herein can also be tested according to othermethods known in the art (see Sarkaria et al, “Inhibition of ATM and ATRKinase Activities by the Radiosensitizing Agent, Caffeine: CancerResearch 59: 4375-5382 (1999); Hickson et al, “Identification andCharacterization of a Novel and Specific Inhibitor of theAtaxia-Telangiectasia Mutated Kinase ATM” Cancer Research 64: 9152-9159(2004); Kim et al, “Substrate Specificities and Identification ofPutative Substrates of ATM Kinase Family Members” The Journal ofBiological Chemistry, 274(53): 37538-37543 (1999); and Chiang et al,“Determination of the catalytic activities of mTOR and other members ofthe phosphoinositide-3-kinase-related kinase family” Methods Mol. Biol.281:125-41 (2004)).

Example 20 ATR Inhibition Assay

Compounds were screened for their ability to inhibit ATR kinase using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgCl₂ and 1 mM DTT. Finalsubstrate concentrations were 10 μM [γ-33P]ATP (3 mCi 33P ATP/mmol ATP,Perkin Elmer) and 800 μM target peptide (ASELPASQPQPFSAKKK).

Assays were carried out at 25° C. in the presence of 5 nM full-lengthATR. An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of ATP and the test compoundof interest. 13.5 μL of the stock solution was placed in a 96 well platefollowed by addition of 2 μL of DMSO stock containing serial dilutionsof the test compound (typically starting from a final concentration of15 μM with 3-fold serial dilutions) in duplicate (final DMSOconcentration 7%). The plate was pre-incubated for 10 minutes at 25° C.and the reaction initiated by addition of 15 μL [γ-33P]ATP (finalconcentration 10 μM).

The reaction was stopped after 24 hours by the addition of 30 μL 0.1Mphosphoric acid containing 2 mM ATP. A multiscreen phosphocellulosefilter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with100 μL 0.2M phosphoric acid prior to the addition of 44 μL of thestopped assay mixture. The plate was washed with 5×200 μL 0.2Mphosphoric acid. After drying, 100 μL Optiphase ‘SuperMix’ liquidscintillation cocktail (Perkin Elmer) was added to the well prior toscintillation counting (1450 Microbeta Liquid Scintillation Counter,Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

Table 5, below, shows the ATR Inhibition Ki values of compounds of thedisclosure. Compounds with a Ki value of <0.01 μM are marked with “+++.”Compounds with a Ki value >0.01 μM but <1 μM are marked with “++.”Compounds with a Ki value >1 μM but <5 μM are marked with “+.”

TABLE 5 Cmpd. # ATR Ki I-N-1 ++ I-N-2 ++ I-N-3 ++ I-N-4 ++ I-N-5 ++I-N-6 — I-N-7 ++ I-N-8 + I-N-9 + I-N-10 ++ I-N-11 ++ I-N-12 ++ I-N-13 ++I-N-14 ++ I-N-15 ++ I-N-16 ++ I-N-17 ++ I-N-18 ++ I-N-19 ++ I-N-20 ++I-N-21 ++ I-N-22 ++ I-N-23 ++ I-N-24 ++ I-N-25 ++ I-N-26 ++ I-N-27 ++I-N-28 ++ I-N-29 ++ I-N-30 ++ I-N-31 + I-N-32 ++ I-N-33 ++ I-N-34 +I-N-35 + I-N-36 + I-N-37 + I-N-38 ++ I-N-39 ++ I-N-40 ++ I-N-41 ++I-N-42 ++ I-N-43 ++ I-N-44 ++ I-N-45 ++ I-N-46 ++ I-N-47 ++ I-N-48 ++I-N-49 ++ I-N-50 ++ I-N-51 ++ I-N-52 + I-N-53 ++ I-N-54 ++ I-N-55 ++I-N-56 ++ I-N-57 ++ I-N-58 ++ I-N-59 ++ I-N-60 ++ I-N-61 ++ I-N-62 ++I-N-63 ++ I-N-64 ++ I-N-65 ++ I-N-66 ++ I-N-67 ++ I-N-68 ++ I-N-69 ++I-N-70 ++ I-N-71 ++ I-N-72 ++ I-N-73 ++ I-N-74 ++ I-N-75 ++ I-N-76 +I-N-77 ++ I-N-78 ++ I-N-79 ++ I-N-80 ++ I-N-81 ++ I-N-82 +++ I-N-83 +++I-N-84 +++ I-N-85 ++ I-N-86 ++ I-N-87 ++ I-N-88 ++ I-N-89 ++ I-N-90 ++I-N-91 +++ I-N-92 + I-N-93 ++ I-N-94 ++ I-N-95 ++ I-N-96 — I-N-97 ++I-N-98 ++ I-N-99 ++ I-N-100 ++ I-N-101 ++ I-N-102 ++ I-N-103 ++ I-N-104++ I-N-105 ++ I-N-106 ++ I-N-107 ++ I-N-108 ++ I-N-109 ++ I-N-110 —I-N-111 + I-N-112 + I-N-113 + I-N-114 — I-N-115 ++ I-N-116 ++ I-N-117 ++I-N-118 ++ I-N-119 ++ I-N-120 ++ I-N-121 ++ I-N-122 ++ I-N-123 ++I-N-124 ++ I-N-125 ++ I-N-126 ++ I-N-127 ++ I-N-128 ++ I-N-129 ++I-N-130 ++ I-N-131 ++ I-N-132 ++ I-N-133 ++ I-N-134 ++ I-N-135 ++I-N-136 ++ I-N-137 ++ I-N-138 + I-N-139 ++ I-N-140 ++ I-N-141 ++I-N-142 + I-N-143 ++ I-N-144 + I-N-145 ++ I-N-146 ++ I-N-147 ++ I-N-148++ I-N-149 ++ I-N-150 ++ I-N-151 + I-N-152 ++ I-N-153 — I-N-154 ++I-N-155 ++ I-N-156 ++ I-N-157 ++ I-N-158 ++ I-N-159 ++ I-N-160 ++I-N-161 ++ I-N-162 ++ I-N-163 ++ I-N-164 ++ I-N-165 ++ I-N-166 ++I-N-167 ++ I-N-168 ++ I-N-169 ++ I-N-170 ++ I-N-171 ++ I-N-172 ++I-N-173 ++ I-N-174 ++ I-N-175 ++ I-N-176 ++ I-N-177 ++ I-N-178 ++I-N-179 ++ I-N-180 ++ I-N-181 ++ I-N-182 ++ I-N-183 ++ I-N-184 ++I-N-185 ++ I-N-186 ++ I-N-187 ++ I-N-188 ++ I-N-189 ++ I-N-190 ++I-N-191 + I-N-192 ++ I-N-193 ++ I-N-194 ++ I-N-195 ++ I-N-196 ++ I-N-197++ I-N-198 ++ I-N-199 ++ I-N-200 ++ I-N-201 ++ I-N-202 ++ I-N-203 ++I-N-204 ++ I-N-205 ++ I-N-206 ++ I-N-207 ++ I-N-208 ++ I-N-209 ++I-N-210 ++ I-N-211 ++ I-N-212 ++ I-N-213 ++ I-N-214 ++ I-N-215 ++I-N-216 ++ I-N-217 ++ I-N-218 ++ I-N-219 ++ I-N-220 ++ I-N-221 ++I-N-222 ++ I-N-223 ++ I-N-224 ++ I-N-225 ++ I-N-226 ++ I-N-227 ++I-N-228 ++ I-N-229 ++ I-N-230 ++ I-N-231 ++ I-N-232 ++ I-N-233 ++I-N-234 ++ I-N-235 ++ I-N-236 ++ I-N-237 ++ I-N-238 ++ I-N-239 ++I-N-240 ++ I-N-241 ++ I-N-242 — I-N-243 ++ I-N-244 ++ I-N-245 — I-N-246++ I-N-247 ++ I-N-248 ++ I-N-249 ++ I-N-250 ++ I-N-251 ++ I-N-252 ++I-N-253 ++ I-N-254 ++ I-N-255 ++ I-N-256 ++ I-N-257 ++ I-N-258 ++I-N-259 + I-N-260 ++ I-N-261 ++ I-N-262 ++ I-N-263 ++ I-N-264 + I-N-265++ I-N-266 ++ I-N-267 ++ I-N-268 ++ I-N-269 ++ I-N-270 ++ I-N-271 ++I-N-272 ++ I-N-273 ++ I-N-274 ++ I-N-275 ++ I-N-276 ++ I-N-277 ++I-N-278 ++ I-N-279 ++ I-N-280 ++ I-N-281 ++ I-N-282 ++ I-N-283 ++I-N-284 ++ I-N-285 ++ I-N-286 ++ I-N-287 ++ I-N-288 ++ I-N-289 + I-N-290++ I-O-1 ++ I-O-2 +++ I-O-3 ++ I-O-4 ++ I-O-5 ++ I-O-6 ++ I-O-7 ++ I-O-8++ I-O-9 ++ I-O-10 ++ I-O-11 ++ I-O-12 ++ I-O-13 ++ I-O-14 ++ I-O-15 ++I-O-16 ++ I-O-17 ++ I-O-18 ++ I-O-19 ++ I-O-20 ++ I-O-21 ++ I-O-22 ++I-O-23 ++ I-O-24 +++ I-O-25 +++ I-O-26 +++ I-O-27 +++ I-O-28 +++ I-O-29+++ I-O-30 +++ I-O-31 +++ I-O-32 +++ I-O-33 +++ I-O-34 +++ I-O-35 +++I-O-36 +++ I-O-37 +++ I-O-38 +++ I-O-39 +++ I-O-40 +++ I-O-41 +++ I-O-42+++ I-O-43 +++ I-O-44 ++ I-O-45 ++ I-O-46 + I-O-47 ++ I-O-48 ++ I-O-49++ I-O-50 ++ I-O-51 ++ I-O-52 + I-O-53 ++ I-O-54 ++ I-O-55 ++ I-O-56 ++I-O-57 ++ I-O-58 ++ I-O-59 ++ I-O-60 ++ I-O-61 ++ I-O-62 ++ I-O-63 ++I-O-64 ++ I-O-65 ++ I-O-66 ++ I-O-67 ++ I-O-68 ++ I-O-69 ++ I-O-70 ++I-O-71 ++ I-O-72 ++ I-O-73 ++ I-O-74 ++ I-O-75 ++ I-O-76 ++ I-O-77 ++I-O-78 ++ I-O-79 — I-O-80 ++ I-O-81 ++ I-O-82 +++ I-O-83 +++ I-O-84 +++I-O-85 ++ I-O-86 +++ I-O-87 ++ I-O-88 ++ I-O-89 ++ I-O-90 ++ I-O-91 ++I-O-92 ++ I-C-1 + I-C-2 + I-C-3 ++ I-C-4 ++ I-C-5 ++ I-C-6 ++ I-C-7 ++I-C-8 ++ I-C-9 ++ I-C-10 ++ I-C-11 ++ I-C-12 ++ I-C-13 + I-C-14 + I-C-15++ I-C-16 ++ I-C-17 ++ I-C-18 ++ I-C-19 ++ I-C-20 ++ I-C-21 ++ I-C-22 ++I-C-23 + I-C-24 ++ I-C-25 ++ I-C-26 ++ I-C-27 ++ I-C-28 ++ I-C-29 ++I-C-30 ++ I-C-31 ++ I-C-32 ++ I-C-33 ++ I-C-34 ++ I-C-35 ++ I-C-36 ++I-C-37 + I-C-38 ++ I-C-39 ++ I-C-40 ++ I-C-41 ++ I-C-42 ++ I-C-43 ++I-C-44 ++ I-C-45 ++ I-C-46 ++ I-C-47 ++ I-C-48 ++ I-C-49 ++ I-C-50 ++I-C-51 ++ I-C-52 ++ I-C-53 ++ I-C-54 ++ I-C-55 ++ I-C-56 ++ I-C-57 ++I-C-58 ++ I-C-59 ++ I-C-60 ++ I-C-61 ++ I-C-62 ++ I-C-63 ++ I-C-64 ++I-C-65 ++ I-C-66 ++ I-C-67 ++ I-C-68 ++ I-C-69 ++ I-C-70 ++ I-C-71 ++I-C-72 ++ I-C-73 ++ I-C-74 ++ I-C-75 ++ I-C-76 + I-C-77 ++ I-C-78 ++I-C-79 ++ I-C-80 ++ I-C-81 +++ I-C-82 ++ I-C-83 ++ I-C-84 ++ I-G-1 ++I-G-2 ++ I-G-3 ++ I-G-4 ++ I-G-5 ++ I-G-6 ++ I-G-7 ++ I-G-8 ++ I-G-9 ++I-G-10 ++ I-G-11 ++ I-G-12 ++ I-G-13 ++ I-G-14 +++ I-G-15 ++ I-G-16 ++I-G-17 + I-G-18 ++ I-G-19 ++ I-G-20 ++ I-G-21 ++ I-G-22 ++ I-G-23 ++I-G-24 ++ I-G-25 ++ I-G-26 ++ I-G-27 ++ I-C-28 ++ I-G-29 ++ I-G-30 ++I-G-31 ++ I-G-32 ++ I-G-33 ++ I-G-34 ++ I-G-35 ++ I-G-36 ++ I-G-37 ++I-G-38 ++ I-G-40 ++ I-G-41 + I-G-42 ++ I-G-43 ++ I-G-44 ++ I-G-45 ++I-G-46 + I-G-47 ++ I-G-48 ++ I-G-49 ++ I-G-50 ++ I-G-51 ++ I-G-52 ++I-G-53 ++ I-G-54 ++ I-G-55 ++ I-G-56 ++ I-G-57 ++ I-G-58 ++ I-G-59 ++I-G-60 ++ I-G-61 ++ I-G-62 ++ I-G-63 ++ I-G-64 ++ I-G-65 ++ I-G-66 ++I-G-67 +++ I-G-68 +++ I-G-69 ++ I-G-70 ++ I-G-71 ++ I-G-72 ++ I-G-73 ++I-G-74 ++ I-G-75 ++ I-G-76 ++ I-G-77 ++ I-G-78 ++ I-G-79 ++ I-G-80 ++I-G-81 ++ I-G-82 ++ I-G-83 ++ I-G-84 ++ I-G-85 ++ I-G-86 ++ I-G-87 ++I-G-88 ++ I-G-89 ++ I-G-90 ++ I-G-91 ++ I-G-92 ++ I-G-93 ++ I-G-94 ++I-G-95 ++ I-G-96 ++ I-G-98 ++ I-G-99 ++

Example 21 Cisplatin Sensitization Assay

Compounds can be screened for their ability to sensitize HCT116colorectal cancer cells to Cisplatin using a 96 h cell viability (MTS)assay. HCT116 cells, which possess a defect in ATM signaling toCisplatin (see, Kim et al.; Oncogene 21:3864 (2002); see also, Takemuraet al.; JBC 281:30814 (2006)) are plated at 470 cells per well in96-well polystyrene plates (Costar 3596) in 150 μl of McCoy's 5A media(Sigma M8403) supplemented with 10% foetal bovine serum (JRH Biosciences12003), Penicillin/Streptomycin solution diluted 1:100 (Sigma P7539),and 2 mM L-glumtamine (Sigma G7513), and allowed to adhere overnight at37° C. in 5% CO₂. Compounds and Cisplatin are then both addedsimultaneously to the cell media in 2-fold serial dilutions from a topfinal concentration of 10 μM as a full matrix of concentrations in afinal cell volume of 200 μl, and the cells are then incubated at 37° C.in 5% CO₂. After 96 h, 40 μl of MTS reagent (Promega G358a) is added toeach well and the cells are incubated for 1 h at 37° C. in 5% CO₂.Finally, absorbance is measured at 490 nm using a SpectraMax Plus 384reader (Molecular Devices) and the concentration of compound required toreduce the IC₅₀ of Cisplatin alone by at least 3-fold (to 1 decimalplace) can be reported.

Table 6, below, shows the Cisplatin sensitization values of compounds ofthe disclosure. Compounds with a Cisplatin sensitization value of <0.02μM are marked with “+++.” Compounds with a Cisplatin sensitizationvalue >0.02 μM but <0.2 μM are marked with “++.” Compounds with aCisplatin sensitization value >0.2 μM but <5 μM are marked with “+.”

TABLE 6 Cmpd. # Cisplatin Sensitization Assay I-N-1 ++ I-N-2 +++ I-N-3+++ I-N-4 +++ I-N-5 ++ I-N-6 — I-N-7 ++ I-N-8 + I-N-9 + I-N-10 ++ I-N-11++ I-N-12 +++ I-N-13 +++ I-N-14 +++ I-N-15 +++ I-N-16 +++ I-N-17 +++I-N-18 ++ I-N-19 +++ I-N-20 +++ I-N-21 +++ I-N-22 — I-N-23 +++ I-N-24+++ I-N-25 — I-N-26 + I-N-27 ++ I-N-28 +++ I-N-29 ++ I-N-30 ++ I-N-31 +I-N-32 ++ I-N-33 + I-N-34 ++ I-N-35 + I-N-36 ++ I-N-37 ++ I-N-38 ++I-N-39 ++ I-N-40 ++ I-N-41 +++ I-N-42 — I-N-43 ++ I-N-44 ++ I-N-45 ++I-N-46 +++ I-N-47 ++ I-N-48 ++ I-N-49 +++ I-N-50 + I-N-51 — I-N-52 ++I-N-53 ++ I-N-54 +++ I-N-55 ++ I-N-56 ++ I-N-57 +++ I-N-58 ++ I-N-59 ++I-N-60 +++ I-N-61 +++ I-N-62 ++ I-N-63 ++ I-N-64 +++ I-N-65 + I-N-66 +++I-N-67 +++ I-N-68 +++ I-N-69 +++ I-N-70 ++ I-N-71 +++ I-N-72 +++ I-N-73+++ I-N-74 +++ I-N-75 +++ I-N-76 +++ I-N-77 + I-N-78 — I-N-79 ++ I-N-80++ I-N-81 +++ I-N-82 ++ I-N-83 ++ I-N-84 +++ I-N-85 ++ I-N-86 +++ I-N-87++ I-N-88 ++ I-N-89 ++ I-N-90 + I-N-91 ++ I-N-92 + I-N-93 — I-N-94 +++I-N-95 ++ I-N-96 — I-N-97 +++ I-N-98 +++ I-N-99 +++ I-N-100 ++ I-N-101++ I-N-102 ++ I-N-103 +++ I-N-104 +++ I-N-105 +++ I-N-106 +++ I-N-107+++ I-N-108 +++ I-N-109 +++ I-N-110 — I-N-111 ++ I-N-112 + I-N-113 +I-N-114 — I-N-115 +++ I-N-116 ++ I-N-117 +++ I-N-118 +++ I-N-119 ++I-N-120 +++ I-N-121 +++ I-N-122 ++ I-N-123 ++ I-N-124 +++ I-N-125 +++I-N-126 +++ I-N-127 +++ I-N-128 +++ I-N-129 — I-N-130 ++ I-N-131 +++I-N-132 +++ I-N-133 ++ I-N-134 + I-N-135 +++ I-N-136 ++ I-N-137 ++I-N-138 ++ I-N-139 +++ I-N-140 +++ I-N-141 +++ I-N-142 ++ I-N-143 ++I-N-144 +++ I-N-145 — I-N-146 +++ I-N-147 +++ I-N-148 +++ I-N-149 +++I-N-150 +++ I-N-151 + I-N-152 +++ I-N-153 ++ I-N-154 +++ I-N-155 +++I-N-156 +++ I-N-157 ++ I-N-158 +++ I-N-159 +++ I-N-160 +++ I-N-161 +I-N-162 ++ I-N-163 +++ I-N-164 +++ I-N-165 +++ I-N-166 +++ I-N-167 +++I-N-168 + I-N-169 +++ I-N-170 +++ I-N-171 +++ I-N-172 +++ I-N-173 +++I-N-174 +++ I-N-175 +++ I-N-176 +++ I-N-177 +++ I-N-178 +++ I-N-179 +++I-N-180 — I-N-181 +++ I-N-182 ++ I-N-183 +++ I-N-184 ++ I-N-185 ++I-N-186 +++ I-N-187 +++ I-N-188 +++ I-N-189 +++ I-N-190 +++ I-N-191 +I-N-192 +++ I-N-193 +++ I-N-194 +++ I-N-195 +++ I-N-196 +++ I-N-197 +++I-N-198 ++ I-N-199 +++ I-N-200 +++ I-N-201 +++ I-N-202 +++ I-N-203 +++I-N-204 — I-N-205 ++ I-N-206 +++ I-N-207 — I-N-208 +++ I-N-209 +++I-N-210 +++ I-N-211 ++ I-N-212 +++ I-N-213 +++ I-N-214 ++ I-N-215 +++I-N-216 +++ I-N-217 ++ I-N-218 + I-N-219 +++ I-N-220 ++ I-N-221 ++I-N-222 ++ I-N-223 ++ I-N-224 + I-N-225 ++ I-N-226 +++ I-N-227 +++I-N-228 +++ I-N-229 +++ I-N-230 +++ I-N-231 +++ I-N-232 ++ I-N-233 ++I-N-234 + I-N-235 ++ I-N-236 +++ I-N-237 + I-N-238 ++ I-N-239 +++I-N-240 ++ I-N-241 +++ I-N-242 + I-N-243 +++ I-N-244 +++ I-N-245 ++I-N-246 ++ I-N-247 +++ I-N-248 ++ I-N-249 +++ I-N-250 ++ I-N-251 +++I-N-252 +++ I-N-253 +++ I-N-254 +++ I-N-255 ++ I-N-256 ++ I-N-257 +++I-N-258 ++ I-N-259 + I-N-260 +++ I-N-261 +++ I-N-262 +++ I-N-263 +I-N-264 + I-N-265 ++ I-N-266 +++ I-N-267 +++ I-N-268 +++ I-N-269 ++I-N-270 +++ I-N-271 +++ I-N-272 +++ I-N-273 +++ I-N-274 +++ I-N-275 +++I-N-276 +++ I-N-277 +++ I-N-278 +++ I-N-279 +++ I-N-280 +++ I-N-281 +++I-N-282 +++ I-N-283 ++ I-N-284 +++ I-N-285 ++ I-N-286 ++ I-N-287 +++I-N-288 +++ I-N-289 ++ I-N-290 ++ I-O-1 +++ I-O-2 ++ I-O-3 ++ I-O-4 ++I-O-5 +++ I-O-6 +++ I-O-7 ++ I-O-8 + I-O-9 ++ I-O-10 +++ I-O-11 +++I-O-12 +++ I-O-13 +++ I-O-14 +++ I-O-15 +++ I-O-16 +++ I-O-17 +++ I-O-18— I-O-19 +++ I-O-20 ++ I-O-21 ++ I-O-22 — I-O-23 +++ I-O-24 ++ I-O-25+++ I-O-26 ++ I-O-27 ++ I-O-28 +++ I-O-29 +++ I-O-30 +++ I-O-31 +++I-O-32 +++ I-O-33 ++ I-O-34 ++ I-O-35 +++ I-O-36 +++ I-O-37 +++ I-O-38+++ I-O-39 +++ I-O-40 ++ I-O-41 +++ I-O-42 +++ I-O-43 +++ I-O-44 ++I-O-45 +++ I-O-46 + I-O-47 + I-O-48 ++ I-O-49 + I-O-50 + I-O-51 —I-O-52 + I-O-53 +++ I-O-54 +++ I-O-55 ++ I-O-56 +++ I-O-57 +++ I-O-58+++ I-O-59 +++ I-O-60 ++ I-O-61 +++ I-O-62 +++ I-O-63 ++ I-O-64 +++I-O-65 +++ I-O-66 + I-O-67 ++ I-O-68 ++ I-O-69 ++ I-O-70 +++ I-O-71 +I-O-72 + I-O-73 + I-O-74 ++ I-O-75 ++ I-O-76 ++ I-O-77 ++ I-O-78 +I-O-79 ++ I-O-80 +++ I-O-81 ++ I-O-82 ++ I-O-83 +++ I-O-84 ++ I-O-85 +++I-O-86 ++ I-O-87 ++ I-O-88 +++ I-O-89 ++ I-O-90 + I-O-91 ++ I-O-92 +++I-C-1 ++ I-C-2 ++ I-C-3 — I-C-4 ++ I-C-5 +++ I-C-6 +++ I-C-7 ++ I-C-8 +I-C-9 + I-C-10 +++ I-C-11 +++ I-C-12 +++ I-C-13 ++ I-C-14 + I-C-15 ++I-C-16 + I-C-17 ++ I-C-18 + I-C-19 ++ I-C-20 +++ I-C-21 +++ I-C-22 ++I-C-23 + I-C-24 +++ I-C-25 +++ I-C-26 ++ I-C-27 ++ I-C-28 — I-C-29 +++I-C-30 +++ I-C-31 +++ I-C-32 — I-C-33 + I-C-34 +++ I-C-35 +++ I-C-36 +++I-C-37 +++ I-C-38 ++ I-C-39 +++ I-C-40 +++ I-C-41 +++ I-C-42 ++ I-C-43+++ I-C-44 +++ I-C-45 +++ I-C-46 + I-C-47 +++ I-C-48 +++ I-C-49 +++I-C-50 +++ I-C-51 ++ I-C-52 ++ I-C-53 +++ I-C-54 +++ I-C-55 + I-C-56 +++I-C-57 +++ I-C-58 +++ I-C-59 ++ I-C-60 ++ I-C-61 +++ I-C-62 ++ I-C-63+++ I-C-64 +++ I-C-65 ++ I-C-66 +++ I-C-67 ++ I-C-68 + I-C-69 +++ I-C-70+++ I-C-71 +++ I-C-72 +++ I-C-73 ++ I-C-74 + I-C-75 ++ I-C-76 + I-C-77+++ I-C-78 ++ I-C-79 +++ I-C-80 +++ I-C-81 +++ I-C-82 +++ I-C-83 ++I-C-84 ++ I-G-1 +++ I-G-2 +++ I-G-3 +++ I-G-4 +++ I-G-5 +++ I-G-6 +++I-G-7 +++ I-G-8 +++ I-G-9 +++ I-G-10 +++ I-G-11 +++ I-G-12 +++ I-G-13+++ I-G-14 +++ I-G-15 +++ I-G-16 +++ I-G-17 + I-G-18 +++ I-G-19 ++I-G-20 + I-G-21 +++ I-G-22 +++ I-G-23 +++ I-G-24 +++ I-G-25 +++ I-G-26++ I-G-27 ++ I-G-28 +++ I-G-29 +++ I-G-30 +++ I-G-31 +++ I-G-32 +++I-G-33 +++ I-G-34 +++ I-G-35 +++ I-G-36 +++ I-G-37 ++ I-G-38 +++ I-G-40+++ I-G-41 +++ I-G-42 +++ I-G-43 +++ I-G-44 +++ I-G-45 +++ I-G-46 +++I-G-47 +++ I-G-48 +++ I-G-49 +++ I-G-50 +++ I-G-51 +++ I-G-52 +++ I-G-53+++ I-G-54 +++ I-G-55 +++ I-G-56 +++ I-G-57 +++ I-G-58 +++ I-G-59 +++I-G-60 +++ I-G-61 +++ I-G-62 +++ I-G-63 +++ I-G-64 +++ I-G-65 +++ I-G-66+++ I-G-67 +++ I-G-68 +++ I-G-69 +++ I-G-70 — I-G-71 — I-G-72 +++ I-G-73+++ I-G-74 +++ I-G-75 +++ I-G-76 +++ I-G-77 +++ I-G-78 +++ I-G-79 +++I-G-80 +++ I-G-81 +++ I-G-82 +++ I-G-83 +++ I-G-84 +++ I-G-85 +++ I-G-86+++ I-G-87 +++ I-G-88 +++ I-G-89 + I-G-90 +++ I-G-91 +++ I-G-92 +++I-G-93 +++ I-G-94 +++ I-G-95 +++ I-G-96 +++ I-G-98 +++ I-G-99 +++

Example 22 Single Agent HCT116 Activity

Compounds can be screened for single agent activity against HCT116colorectal cancer cells using a 96 h cell viability (MTS) assay. HCT116are plated at 470 cells per well in 96-well polystyrene plates (Costar3596) in 150 μl of McCoy's 5A media (Sigma M8403) supplemented with 10%foetal bovine serum (JRH Biosciences 12003), Penicillin/Streptomycinsolution diluted 1:100 (Sigma P7539), and 2 mM L-glumtamine (SigmaG7513), and allowed to adhere overnight at 37° C. in 5% CO₂. Compoundsare then added to the cell media in 2-fold serial dilutions from a topfinal concentration of 10 μM as a full matrix of concentrations in afinal cell volume of 2004 and the cells are then incubated at 37° C. in5% CO₂. After 96 h, 40 μl of MTS reagent (Promega G358a) is added toeach well and the cells are incubated for 1 h at 37° C. in 5% CO₂.Finally, absorbance is measured at 490 nm using a SpectraMax Plus 384reader (Molecular Devices) and 1050 values can be calculated.

Example 23 ATR-complex Inhibition Assay

Compounds were screened for their ability to inhibit ATR kinase, in thepresence of partner proteins ATRIP, CLK2 and TopBP1, using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgCl₂ and 1 mM DTT. Finalsubstrate concentrations were 10 μM [g-33P]ATP (3.5 μCi 33P ATP/nmolATP, Perkin Elmer, Massachusetts, USA) and 800 μM target peptide(ASELPASQPQPFSAKKK, Isca Biochemicals, Cambridgeshire, UK).

Assays were carried out at 25° C. in the presence of 4 nM full-lengthATR, 40 nM full-length ATRIP, 40 nM full-length CLK2 and 600 nM TopBP1(A891-S1105). An enzyme stock buffer solution was prepared containingall of the reagents listed above, with the exception of target peptide,ATP and the test compound of interest. This enzyme stock waspre-incubated for 30 minutes at 25° C. 8.5 μL of the enzyme stocksolution was placed in a 96-well plate followed by addition of 5 μl oftarget peptide and 2 μL of DMSO stock containing serial dilutions of thetest compound (typically starting from a final concentration of 1.5 μMwith 2.5-fold serial dilutions) in duplicate (final DMSO concentration7%). The plate was pre-incubated for 10 minutes at 25° C. and thereaction initiated by addition of 15 μL [g-33P]ATP (final concentration10 μM).

The reaction was stopped after 20 hours by the addition of 30 μL 0.3 Mphosphoric acid containing 2 mM ATP. A phosphocellulose filter 96-wellplate (Multiscreen HTS MAPHNOB50, Merck-Millipore, Massachusetts, USA)was pretreated with 100 μL 0.1 M phosphoric acid prior to the additionof 45 μL of the stopped assay mixture. The plate was washed with 5×200μL 0.1 M phosphoric acid. After drying, 50 μL Optiphase ‘SuperMix’liquid scintillation cocktail (Perkin Elmer, Massachusetts, USA) wasadded to the well prior to scintillation counting (Wallac 1450 MicrobetaLiquid Scintillation Counter, Perkin Elmer, Massachusetts, USA).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 6.0c for Macintosh, GraphPad Software Inc., San Diego, USA).

Table 7, below, shows the Cisplatin sensitization values of compounds ofthe disclosure. Compounds with a Cisplatin sensitization value of <0.02μM are marked with “+++.” Compounds with a Ki value >0.02 μM but <0.2 μMare marked with “++.” Compounds with a Ki value >0.2 μM but <5 μM aremarked with “+.”

TABLE 7 Cmpd. # ATR Ki I-N-1 +++ I-N-13 +++ I-N-58 +++ I-N-118 +++I-N-166 +++ I-N-186 +++ I-N-275 +++ I-C-25 +++ I-C-31 +++ I-C-43 +++I-C-79 +++ I-G-4 +++ I-G-7 +++ I-G-12 +++ I-G-21 +++ I-G-32 +++

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds, methods, and processes of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments that have been represented by way of exampleherein.

We claim:
 1. A process for preparing a compound of formula I-G-32:

or a salt thereof, comprising reacting a compound of formula 6a:

or a salt thereof, with a substituted 3-aminopyridine under suitableconditions to form an amide bond.
 2. The process of claim 1, furthercomprising a step of preparing the compound of formula 6a:

or a salt thereof, comprising reacting a compound of formula 5a:

or a salt thereof, under suitable conditions to form an activated ester.3. The process of claim 2, further comprising a step of preparing thecompound of formula 5a:

or a salt thereof, comprising reacting a compound of formula 4a:

or a salt thereof, under suitable deprotection conditions, wherein Allis allyl.
 4. The process of claim 3, further comprising a step ofpreparing the compound of formula 4a:

or a salt thereof, comprising reacting a compound of formula 3:

or a salt thereof, under suitable condensation conditions to form apyrimidine ring.
 5. The process of claim 4, further comprising a step ofpreparing the compound of formula 3:

or a salt thereof, comprising reacting a compound of formula 2:

or a salt thereof, under suitable condensation conditions to form apyrazole ring.
 6. The process of claim 5, further comprising a step ofpreparing the compound of formula 2:

or a salt thereof, comprising reacting a compound of formula 1:

under suitable anion condensation conditions.